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1.  Dose-Levels and First Signs of Efficacy in Contemporary Oncology Phase 1 Clinical Trials 
PLoS ONE  2011;6(3):e16633.
Phase 1 trials play a crucial role in oncology by translating laboratory science into efficient therapies. Molecular targeted agents (MTA) differ from traditional cytotoxics in terms of both efficacy and toxicity profiles. Recent reports suggest that higher doses are not essential to produce the optimal anti-tumor effect. This study aimed to assess if MTA could achieve clinical benefit at much lower dose than traditional cytotoxics in dose seeking phase 1 trials.
Patients and Methods
We reviewed 317 recent phase 1 oncology trials reported in the literature between January 1997 and January 2009. First sign of efficacy, maximum tolerated dose (MTD) and their associated dose level were recorded in each trial.
Trials investigating conventional cytotoxics alone, MTA alone and combination of both represented respectively 63.0% (201/317), 23.3% (74/317) and 13.7% (42/317) of all trials. The MTD was reached in 65.9% (209/317) of all trials and was mostly observed at the fifth dose level. First sign of efficacy was less frequently observed at the first three dose-levels for MTA as compared to conventional cytotoxics or combinations regimens (48.3% versus 63.2% and 61.3%). Sign of efficacy was observed in the same proportion whatever the treatment type (73–82%). MTD was less frequently established in trials investigating MTA alone (51.3%) or combinations (42.8%) as compared to conventional cytotoxic agents (75.6%).
First sign of efficacy was less frequently reported at the early dose-levels and MTD was less frequently reached in trials investigating molecular targeted therapy alone. Similar proportion of trials reported clinical benefit.
PMCID: PMC3056556  PMID: 21415927
2.  Antitumor Activity of Rapamycin in a Phase I Trial for Patients with Recurrent PTEN-Deficient Glioblastoma 
PLoS Medicine  2008;5(1):e8.
There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population.
Methods and Findings
Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN) loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR), we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation) varied substantially. Tumor cell proliferation (measured by Ki-67 staining) was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test) but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy (p < 0.05, Logrank test).
Rapamycin has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3K pathway inhibitors. The short-term treatment endpoints used in this neoadjuvant trial design identified the importance of monitoring target inhibition and negative feedback to guide future clinical development.
Trial registration: (#NCT00047073).
In a Phase I clinical trial Charles Sawyers and colleagues investigated the role of rapamycin in patients with PTEN-deficient glioblastoma.
Editors' Summary
Glioblastoma is a highly malignant tumor of the brain. As with other tumors, it can result from a number of different molecular changes. Traditional chemotherapy does little more than contain these tumors, and cannot cure it. An alternative approach to the treatment of such tumors is to target specific molecular changes in the tumor. Obviously such targeted treatment will work only in patients who have the specific molecular defect being targeted. Hence, traditional clinical trials, which include a large variety of different patients and tumors with different genetic changes, may be an inappropriate way to test how effective targeted treatments are.
One specific change that has been identified in around 40% of patients with glioblastoma is inactivation of a gene known as PTEN, which acts as a tumor suppressor gene. When PTEN is inactivated it has previously been shown to make cells more sensitive to a class of drugs known as mTOR inhibitors—one of which is rapamycin (trade name Sirolimus). mTOR is a protein that is involved in the regulation of a number of cellular processes including growth and proliferation. Drugs active against mTOR are currently being tested for effectiveness against other cancers and as immunosuppressive agents.
Why Was This Study Done?
This was a Phase I study—that is, the earliest type of a drug study that is done in humans—which aimed to look at the safety of rapamycin in a selected group of patients who were undergoing surgery after recurrence of glioblastoma, and whose tumors did not express PTEN. In addition, the authors also wanted to assess the feasibility of incorporating detailed molecular studies of the action of this drug into such a Phase I study and whether these molecular studies could predict whether patients were more or less likely to respond to rapamycin.
What Did the Researchers Do and Find?
A total of 15 patients were treated with rapamycin at differing doses for one week before surgery and then again after surgery until there was evidence that the tumors were progressing. There was no evidence of very severe toxicity in any of the patients, though there were some adverse effects that required treatment. When samples from the patients were tested after surgery, seven of them showed a reduction in how rapidly the tumor cells divided, and this reduction was associated with how much inhibition there was of mTOR. Two of these patients showed evidence on scans of a reduction in tumor mass. Cells from tumors that appeared resistant to rapamycin in patients were sensitive to rapamycin in tissue culture, suggesting that the lack of response was due to the drug not being able to penetrate the tumor. A second, unfortunate effect of rapamycin was to cause activation of another intracellular protein, Akt, in some patients; when this activation occurred, patients had a shorter time between surgery and a return of their disease.
What Do These Findings Mean?
The detailed molecular studies within this Phase I trial allow a better understanding of how this targeted drug works. These findings suggest that the rapamycin can reduce the proliferation rate of glioblastoma cells, and that this reduction appears to be related to how well the drug is able to penetrate the tumor and inhibit mTOR. However, in some patients the activation of a second pathway can speed up the course of the disease, so further trials should incorporate inhibitors of this second pathway.
Additional Information.
Please access these Web sites via the online version of this summary at
The US National Cancer Institute provides information on all aspects of cancer (in English and Spanish)
The UK charity Cancerbackup provides information on brain tumors
Wikipedia has a page on mTOR (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC2211560  PMID: 18215105
3.  Phase I Oncology Studies: Evidence That in the Era of Targeted Therapies, Patients on Lower Doses Do Not Fare Worse 
To safely assess new drugs, cancer patients in initial cohorts of phase I oncology studies receive low drug doses. Doses are successively increased until the maximum tolerated dose (MTD) is determined. Since traditional chemotherapy is often more effective near the MTD, ethical concerns have been raised regarding administration of low drug doses to phase I patients. However, a substantial portion of oncology trials now investigate targeted agents, which may have different dose-response relationships than cytotoxic chemotherapies.
Twenty-four consecutive trials treating 683 patients between 10-01-2004 and 6-30-2008 at MD Anderson Cancer Center were analyzed. Patients were assigned to a low-dose (≤25% MTD), medium-dose (25–75% MTD), or high-dose (≥75% MTD) group, and groups were compared for response rate, time-to-treatment-failure, progression-free survival, overall survival, and toxicity. To remove negatively biasing data from the high-dose group, in a second analysis patients treated above the MTD were excluded (high-dose group = 75–100% MTD). 97.7% of patients received targeted agents.
Even when excluding patients above the MTD, there was an early trend favoring the low- versus high-dose group in time-to-treatment-failure, with 32.9% versus 25.2% of patients on therapy at 3 months (p=0.08). Additionally, the low-dose group fared at least as well as the other groups in all other outcomes, including response rate, progression-free survival, overall survival, and toxicity.
These data may help alleviate concerns that patients who receive low drug doses on contemporary phase I oncology trials fare worse, and suggest targeted agents may have different dose-response relationships than cytotoxic chemotherapies.
PMCID: PMC2822881  PMID: 20145187
4.  Effect of Folic Acid and Vitamin B12 on Pemetrexed Antifolate Chemotherapy in Nutrient Lung Cancer Cells 
BioMed Research International  2013;2013:389046.
Pemetrexed (MTA) is a multitargeted antifolate drug approved for lung cancer therapy. Clinically, supplementation with high doses of folic acid (FA) and vitamin B12 (VB12) lowers MTA cytotoxicities. An antagonistic effect of FA/VB12 on MTA efficacy has been proposed. However, patients who receive FA/VB12 show better tolerance to MTA with improved survival. The aims of this study are to investigate the modulation of FA and VB12 on MTA drug efficacy in human nonsmall cell lung cancer (NSCLC) cell lines. The sensitivities of cells, apoptosis, and MTA-regulated proteins were characterized to determine the possible effects of high doses of FA and VB12 on MTA efficacy. MTA has the lowest efficacy under 10% serum conditions. However, supplementation with FA and VB12 individually and additively reversed the insensitivity of NSCLC cells to MTA treatment with 10% serum. The enhanced sensitivities of cells following FA/VB12 treatment were correlated with increasing apoptosis and were specific to MTA but not to 5-fluorouracil (5-FU). Enhanced sensitivity was also associated with p21WAF1/Cip1 expression level. Our results revealed no antagonistic effect of high doses of FA/VB12 on MTA efficacy in cancer cells grown in nutrient medium. Furthermore, these data may partially explain why supplementation of FA and VB12 resulted in better survival in MTA-treated patients.
PMCID: PMC3747471  PMID: 23984356
5.  Clinical Development of VEGF Signaling Pathway Inhibitors in Childhood Solid Tumors 
The Oncologist  2011;16(11):1614-1625.
The clinical development of vascular endothelial growth factor signaling pathway inhibitors in pediatric solid tumors is reviewed. Challenges and considerations for future trials of antiangiogenic agents in children and adolescents are discussed.
Learning Objectives
After completing this course, the reader will be able to: Identify the mechanism, specificity, relative potency, dosing schedule, important pharmacokinetic characteristics, and agent-specific side effects of the VEGF signaling pathway inhibitors currently in pediatric development.Describe the different concerns between children and adults regarding the common class side effects of the VEGF pathway inhibitors.
This article is available for continuing medical education credit at
Angiogenesis is a target shared by both adult epithelial cancers and the mesenchymal or embryonal tumors of childhood. Development of antiangiogenic agents for the pediatric population has been complicated by largely theoretical concern for toxicities specific to the growing child and prioritization among the many antiangiogenic agents being developed for adults. This review summarizes the mechanism of action and preclinical data relevant to childhood cancers and early-phase clinical trials in childhood solid tumors. Single-agent adverse event profiles in adults and children are reviewed with emphasis on cardiovascular, bone health, and endocrine side effects. In addition, pharmacological factors that may be relevant for prioritizing clinical trials of these agents in children are reviewed. Considerations for further clinical evaluation should include preclinical data, relative potency, efficacy in adults, and the current U.S. Food and Drug Administration approval status. Toxicity profiles of vascular endothelial growth factor (VEGF) signaling pathway inhibitors may be age dependent and ultimately, their utility in the treatment of childhood cancer will require combination with standard cytotoxic drugs or other molecularly targeted agents. In combination studies, toxicity profiles, potential drug interactions, and late effects must be considered. Studies to assess the long-term impact of VEGF signaling pathway inhibitors on cardiovascular, endocrine, and bone health in children with cancer are imperative if these agents are to be administered to growing children and adolescents with newly diagnosed cancers.
PMCID: PMC3233297  PMID: 22042784
Angiogenesis inhibitors; Childhood cancer; VEGF; Drug development
6.  Targeting of Interferon-Beta to Produce a Specific, Multi-Mechanistic Oncolytic Vaccinia Virus 
PLoS Medicine  2007;4(12):e353.
Oncolytic viruses hold much promise for clinical treatment of many cancers, but a lack of systemic delivery and insufficient tumor cell killing have limited their usefulness. We have previously demonstrated that vaccinia virus strains are capable of systemic delivery to tumors in mouse models, but infection of normal tissues remains an issue. We hypothesized that interferon-beta (IFN-β) expression from an oncolytic vaccinia strain incapable of responding to this cytokine would have dual benefits as a cancer therapeutic: increased anticancer effects and enhanced virus inactivation in normal tissues. We report the construction and preclinical testing of this virus.
Methods and Findings
In vitro screening of viral strains by cytotoxicity and replication assay was coupled to cellular characterization by phospho-flow cytometry in order to select a novel oncolytic vaccinia virus. This virus was then examined in vivo in mouse models by non-invasive imaging techniques. A vaccinia B18R deletion mutant was selected as the backbone for IFN-β expression, because the B18R gene product neutralizes secreted type-I IFNs. The oncolytic B18R deletion mutant demonstrated IFN-dependent cancer selectivity and efficacy in vitro, and tumor targeting and efficacy in mouse models in vivo. Both tumor cells and tumor-associated vascular endothelial cells were targeted. Complete tumor responses in preclinical models were accompanied by immune-mediated protection against tumor rechallenge. Cancer selectivity was also demonstrated in primary human tumor explant tissues and adjacent normal tissues. The IFN-β gene was then cloned into the thymidine kinase (TK) region of this virus to create JX-795 (TK−/B18R−/IFN-β+). JX-795 had superior tumor selectivity and systemic intravenous efficacy when compared with the TK−/B18R− control or wild-type vaccinia in preclinical models.
By combining IFN-dependent cancer selectivity with IFN-β expression to optimize both anticancer effects and normal tissue antiviral effects, we were able to achieve, to our knowledge for the first time, tumor-specific replication, IFN-β gene expression, and efficacy following systemic delivery in preclinical models.
Stephen Thorne and colleagues describe, in a mouse model, an oncolytic vaccinia virus with interferon-dependent cancer selectivity that allows tumor-specific replication; it also expresses the IFN-β gene and hence has efficacy against tumors.
Editors' Summary
Normally, throughout life, cell division (which produces new cells) and cell death are carefully balanced to keep the body in good working order. But sometimes cells acquire changes (mutations) in their genetic material that allow them to divide uncontrollably to form cancers—disorganized masses of cells. Cancers can develop anywhere in the body and, as they develop, their cells acquire other genetic changes that enable them to move and start new tumors (metastases) elsewhere. Chemotherapy drugs kill rapidly dividing cancer cells but, because some normal cells are also sensitive to these drugs, it is hard to destroy the cancer without causing serious side effects. Consequently, researchers are trying to develop “targeted” therapies that attack the changes in cancer cells that allow them to divide uncontrollably but leave normal cells unscathed. One promising class of targeted therapies is oncolytic viruses. These viruses make numerous copies of themselves inside cancer cells (but not inside normal cells). Eventually the cancer cell bursts open (lyses), releases more of the therapeutic agent, and dies.
Why Was This Study Done?
Existing oncolytic viruses have two major disadvantages: they have to be injected directly into tumors, and therefore they can't destroy distant metastases; and they don't kill cancer cells particularly efficiently. In this study, the researchers have tried to adapt vaccinia virus (a virus that infects humans and which has recently been shown to kill tumor cells when injected into the bloodstream) in two ways: to both infect cancer cells selectively and then to kill them effectively.
They hypothesized that putting a gene that causes expression of a protein called interferon-beta (IFN-β) in a particular virus strain that is itself incapable of responding to IFN-β might achieve these aims. Human cells infected with viruses usually release IFNs, which induce an antiviral state in nearby cells. But vaccinia virus makes anti-IFN proteins that prevent IFN release. If the viral genes that encode these proteins are removed from the virus, the virus cannot spread through normal cells. However, many cancer cells have defective IFN signaling pathways so the virus can spread through them. IFN-β expression by the virus, however, should improve its innate anticancer effects because IFN-β stops cancer cells dividing, induces an antitumor immune response, and stops tumors developing good blood supplies.
What Did the Researchers Do and Find?
The researchers selected a vaccinia virus strain called WR-delB18R in which the B18R gene, which encodes an anti-IFN protein, had been removed from the virus. (WR is a wild-type virus.) In laboratory experiments, IFN treatment blocked the spread of WR-delB18R in normal human cells but not in human tumor cells. After being injected into the veins of tumor-bearing mice, WR-delB18R was rapidly cleared from normal tissues but persisted in the tumors. A single injection of WR-delB18R directly into the tumor killed most of the tumor cells. A similar dose injected into a vein was less effective but nevertheless increased the survival time of some of the mice by directly killing the tumor cells, by targeting the blood supply of the tumors, and by inducing antitumor immunity. Finally, when the researchers inserted the IFN-β gene into this WR-delB18R, the new virus—JX-795—was much better at killing tumors after intravenous injection than either WR or WR-delB18R.
What Do These Findings Mean?
These findings indicate that the vaccinia virus can be adapted so that it replicates only in tumor cells and kills these cells effectively after intravenous injection. In particular, they show that the strategy adopted by the researchers both optimizes the anticancer effects of the virus and minimizes viral replication in normal tissues. JX-795 is a promising oncolytic virus, therefore, particularly since vaccinia virus has been safely used for many years to vaccinate people against smallpox. Nevertheless, it will be some years before JX-795 can be used clinically. Vaccinia virus constructs like this need to be tested extensively in the laboratory and in animals before any attempt is made to test them in people and, even if they passes all these preclinical tests with flying colors, only clinical trials will reveal whether they can treat human cancer. Several related strains of vaccinia virus are currently undergoing clinical testing.
Additional Information.
Please access these Web sites via the online version of this summary at
The US National Cancer Institute provides information on all aspects of cancer (in English and Spanish)
CancerQuest, from Emory University, provides information on all aspects of cancer (in several languages)
The UK charity Cancerbackup also provides information on all aspects of cancer
Wikipedia has a page on oncolytic viruses (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
A short interview about oncolytic viruses with researcher Dr. John Bell is available on the Insidermedicine Web site
The Oncolytic virus Web page provides lists of oncolytic viruses classified by type
PMCID: PMC2222946  PMID: 18162040
7.  Clinical studies with MTA. 
British Journal of Cancer  1998;78 (Suppl 3):35-40.
MTA (LY231514), a multi-targeted antifolate, is a classical antifolate undergoing intracellular polyglutamation. Polyglutamated MTA is a potent thymidylate synthase (TS) inhibitor and inhibits other folate-dependent enzymes, including dihydrofolate reductase and glycinamide ribonucleotide formyl transferase. Multifocal antifolates may overcome antifolate resistance, but it is not known whether the anti-tumour activity of MTA depends on its TS inhibition, its primary locus of action, or whether other loci contribute. MTA was examined in three phase I trials using different schedules: a 10-min i.v. infusion given once every 3 weeks, once weekly for 4 weeks every 6 weeks or daily for 5 days every 3 weeks. Dose-limiting toxicities were neutropenia and thrombocytopenia. Other consistently seen side-effects, which were manageable, included mucositis, skin rashes and transient elevations of transaminases. Toxicity was highly schedule dependent: the recommended dose for the 3-weekly schedule (600 mg m(-2)) was 30 times that for the daily x 5 schedule (4 mg m(-2)day(-1)). The 3-weekly dosing schedule was chosen for phase II evaluation. Phase II trials are underway to investigate the activity and toxicity of MTA in several tumour types, including colorectal, pancreas, breast, bladder and non-small-cell lung cancer (NSCLC) Further phase I trials will investigate MTA in combination with other agents, including gemcitabine, cisplatin, 5-fluorouracil and folate. Preliminary phase II trials results are encouraging; responses were seen in colorectal, pancreas, NSCLC and breast cancer.
PMCID: PMC2062802  PMID: 9717989
8.  Effective Treatment of Advanced Human Melanoma Metastasis in Immunodeficient Mice Using Combination Metronomic Chemotherapy Regimens 
Statement of translational relevance
Despite significant efforts over the last two decades aimed at improving the efficacy of standard treatment (maximum tolerated dose (MTD) of dacarbazine), there has been no significant increase in the median survival of patients suffering from metastatic melanoma. Given the lack of success achieved, a rethinking of alternative treatment strategies is needed. Using preclinical models of advanced melanoma metastasis, we show that metronomic chemotherapeutic combinations results in improved survival, which is achieved with minimal toxicity. These results compare favorably with minimal effectiveness achieved by MTD dacarbazine therapy (alone or in combination with other chemotherapeutic agents or a VEGFR-blocking antibody), often accompanied by higher toxicity. Successes in preclinical setting of metastatic breast cancer have led to a clinical trial to examine the efficacy of metronomic therapy. A similar extension of the metronomic chemotherapeutic combinations presented here into the clinical setting of melanoma metastasis may be warranted.
The development of effective therapeutic approaches for treatment of metastatic melanoma remains an immense challenge. Present therapies offer minimal benefit. While dacarbazine (DTIC) chemotherapy remains the standard therapy, it mediates only low response rates, usually of short duration, even when combined with other chemotherapeutic agents. Thus, new therapeutic strategies are urgently needed.
Experimental design
Using a newly developed preclinical model, we evaluated the efficacy of various doublet metronomic combination chemotherapy against established, advanced melanoma metastasis and compared these to the standard maximum tolerated dose (MTD) DTIC (alone or in combination with chemotherapeutic agents or VEGFR-blocking antibody)
Whereas MTD DTIC therapy did not cause significant improvement in median survival, a doublet combination of low-dose metronomic (LDM) vinblastine (Vbl) and LDM cyclophosphamide (CTX) induced a significant increase in survival with only minimal toxicity. Furthermore, we show that the incorporation of the LDM Vbl/LDM CTX combination with a LDM DTIC regimen also results in a significant increase in survival, but not when combined with MTD DTIC therapy. We also show that a combination of metronomic Vbl therapy and a VEGFR2-blocking antibody (DC101) results in significant control of metastatic disease and that the combination of LDM Vbl/DC101 and LDM DTIC induced a significant improvement in median survival.
The effective control of advanced metastatic melanoma achieved by these metronomic-based chemotherapeutic approaches warrants clinical consideration of this treatment concept given the recent results of a number of metronomic-based chemotherapy clinical trials.
PMCID: PMC2743327  PMID: 19622578
melanoma; spontaneous metastasis; vinblastine; cyclophosphamide; DC101; metronomic chemotherapy
9.  OPC-67683, a Nitro-Dihydro-Imidazooxazole Derivative with Promising Action against Tuberculosis In Vitro and In Mice 
PLoS Medicine  2006;3(11):e466.
Tuberculosis (TB) is still a leading cause of death worldwide. Almost a third of the world's population is infected with TB bacilli, and each year approximately 8 million people develop active TB and 2 million die as a result. Today's TB treatment, which dates back to the 1970s, is long and burdensome, requiring at least 6 mo of multidrug chemotherapy. The situation is further compounded by the emergence of multidrug-resistant TB (MDR-TB) and by the infection's lethal synergy with HIV/AIDS. Global health and philanthropic organizations are now pleading for new drug interventions that can address these unmet needs in TB treatment.
Methods and Findings
Here we report OPC-67683, a nitro-dihydro-imidazooxazole derivative that was screened to help combat the unmet needs in TB treatment. The compound is a mycolic acid biosynthesis inhibitor found to be free of mutagenicity and to possess highly potent activity against TB, including MDR-TB, as shown by its exceptionally low minimum inhibitory concentration (MIC) range of 0.006–0.024 μg/ml in vitro and highly effective therapeutic activity at low doses in vivo. Additionally, the results of the post-antibiotic effect of OPC-67683 on intracellular Mycobacterium tuberculosis showed the agent to be highly and dose-dependently active also against intracellular M. tuberculosis H37Rv after a 4-h pulsed exposure, and this activity at a concentration of 0.1 μg/ml was similar to that of the first-line drug rifampicin (RFP) at a concentration of 3 μg/ml. The combination of OPC-67683 with RFP and pyrazinamide (PZA) exhibited a remarkably quicker eradication (by at least 2 mo) of viable TB bacilli in the lung in comparison with the standard regimen consisting of RFP, isoniazid (INH), ethambutol (EB), and PZA. Furthermore, OPC-67683 was not affected by nor did it affect the activity of liver microsome enzymes, suggesting the possibility for OPC-67683 to be used in combination with drugs, including anti-retrovirals, that induce or are metabolized by cytochrome P450 enzymes.
We concluded that based on these properties OPC-67683 has the potential to be used as a TB drug to help combat the unmet needs in TB treatment.
A nitro-dihydro-imidazooxazole derivative was shown to have the potential for use against tuberculosis.
Editors' Summary
One-third of the world's population is infected with Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB). Most infected people are healthy—the bacteria can remain latent for years, hidden within cells in the body. However, every year 8 million people develop active TB, a chronic disease that usually affects the lungs, and 2 million people die. For most of the second half of the 20th century, TB was in decline because of the powerful antibiotics that were developed from the 1940s onwards. The standard treatment for TB—four antibiotics that have to be taken several times a week for at least six months to flush out any latent M. tuberculosis bacteria—was introduced in the late 1970s and saved many lives. Recently, however, efforts to eradicate TB have been set back by the HIV/AIDS epidemic—people with damaged immune systems are very susceptible to TB—and the emergence of multi-drug resistant (MDR) bacteria.
Why Was This Study Done?
The treatment for TB is long and unpleasant, and patients who develop MDR-TB have to be treated with second-line drugs that are less effective, more expensive, and more toxic. In addition, for people infected with both HIV and TB, some antiretroviral and anti-TB drugs cannot be used at the same time. Many drugs are either activated or removed by enzymes in the liver, so combinations of these two classes of drugs sometimes alter liver function in a way that causes clinical problems. There is, therefore, an urgent need for new, effective anti-TB drugs that attack M. tuberculosis in a different way than do existing drugs. Such drugs should ideally be active against MDR M. tuberculosis, work quickly at low doses, be active against latent bacteria, and have minimal effects on the liver so that they can be used in patients co-infected with HIV. In this study, the researchers investigated a chemical called OPC-67683.
What Did the Researchers Do and Find?
The researchers identified a compound that inhibited the production of mycolic acid—an essential component of the cell wall of M. tuberculosis—and they tested its ability to kill the organism. They then tested in detail its ability to inhibit bacterial growth in dishes of antibiotic-sensitive and MDR M. tuberculosis and isolates from patients. OPC-67683 inhibited the growth of all these bugs at lower concentrations than the four antibiotics used in the standard TB treatment. It also killed bacteria hidden within human cells as well as or better than these drugs. Next, the researchers treated mice infected with M. tuberculosis with OPC-67683. They found that it reduced the number of bacteria in the lungs of both normal and immunocompromised mice at lower concentrations than the standard drugs. Furthermore, when combined with two of the standard drugs, it reduced the time taken to clear bacteria from the lungs by the standard drug regimen by two months. Finally, the researchers showed that OPC-67683 had no effects on the liver enzymes that metabolize antiretrovirals, and, conversely, that the activity of OPC-67683 was not affected by liver enzymes. Thus, this agent is unlikely to cause clinical problems or lose its efficacy in HIV patients who are receiving antiretroviral drugs.
What Do These Findings Mean?
These results from laboratory and animal experiments suggest that OPC-67683 could possibly fulfill the criteria for a new anti-TB drug. OPC-67683 is active against MDR-TB. It is also active against intracellular TB, which the authors postulate could be a positive link with the effective treatment of latent TB, and it works quickly in animals when combined with existing anti-TB drugs. Importantly, it also disables M. tuberculosis in a unique way and does not appear to have any major effects on the liver that might stop it from being used in combination with antiretrovirals. All these preclinical characteristics now need to be checked in people—many drugs do well in preclinical studies but fail in patients. These clinical studies need to be expedited given the upsurge in TB, and, write the researchers, OPC-67683 needs to be tested in combination with both conventional drugs and other new drugs so that the best regimen of new drugs for the treatment of TB can be found as soon as possible.
Additional Information.
Please access these Web sites via the online version of this summary at
US National Institute of Allergy and Infectious Diseases patient fact sheet on tuberculosis
US Centers for Disease Control and Prevention information on tuberculosis
MedlinePlus encyclopedia entry on tuberculosis
NHS Direct Online patient information on tuberculosis from the UK National Health Service
World Health Organization information on the global elimination of tuberculosis
Global Alliance for TB Drug Development information on why new TB drugs are needed
PMCID: PMC1664607  PMID: 17132069
10.  Perspectives on the Design of Clinical Trials Combining Transarterial Chemoembolization and Molecular Targeted Therapy 
Liver Cancer  2012;1(3-4):168-176.
Transarterial chemoembolization (TACE) moderately prolongs the survival of patients with intermediate-stage hepatocellular carcinoma. Molecular targeted therapy (MTT) may improve the efficacy of TACE. However, the findings of clinical trials evaluating the efficacy of a combination of TACE and MTT are conflicting. We hypothesized that this disparity can be prevented using alternative study designs. In this review, we classify the pertinent issues of study designs into five domains: primary endpoints, patients, TACE procedures, timing of randomization, and drug administration. Furthermore, we discuss the methods for increasing the success rate by minimizing potentially confounding factors within these five domains. Transarterial chemoembolization (TACE) is the current standard therapy for patients with Barcelona Clinic Liver Cancer (BCLC) intermediate-stage hepatocellular carcinoma (HCC) [1, 2, 3]. The survival benefit of TACE is supported by the results of meta-analysis of clinical trials comparing TACE with other conservative treatments in patients with inoperable HCC [4]. The results showed that the median survival of patients improved from approximately 16 to 20 months following TACE [4, 5]. Although advances in TACE techniques and the use of new embolization agents may improve the efficacy of TACE [6, 7], other approaches are needed to further improve the outcome in HCC patients treated using TACE. Molecular targeted therapy (MTT) has improved the survival of patients with advanced-stage HCC [5, 8]. Therefore, combining MTT and TACE may additionally improve the survival in patients with intermediate-stage HCC. Many molecular targeted agents (MTA) are currently undergoing evaluation in randomized trials (table 1). However, the designs of these trials differ significantly. The results of two trials combining sorafenib and TACE were recently reported. Both trials failed to demonstrate a therapeutic benefit of the combination therapy for time to tumor progression (TTP) or overall survival (OS) [9, 10]. However, specific subgroups of patients who received treatment for more than 6 months exhibited significantly better survival (table 2). Because median survival can be greater than 2 years in patients with intermediate-stage HCC, it is likely that an extended exposure period is necessary for MTA effects to reach the biological threshold at which survival benefit becomes measurable. Therefore, early discontinuation of study drug treatment may significantly undermine the statistical power of efficacy analysis in randomized trials (fig. 1). Clinical trials should be designed to minimize confounding factors that could lead to early discontinuation of study drug [1, 2, 3, 11, 12]. Factors that are crucial in this regard can be categorized into five domains: (1) selection of primary endpoints, (2) selection of patient population, (3) selection of TACE procedures, (4) timing of randomization, and (5) study drug administration. In this review we discuss the confounding effects potentially associated with each domain and the possible interactions among domains in trials combining TACE and MTA. We also discuss strategies that can help improve sensitivity and accuracy measurements of MTA efficacy.
PMCID: PMC3760466  PMID: 24159581
Clinical trial; Hepatocellular carcinoma; Transarterial chemoembolization
11.  Safety and efficacy of targeted agents in metastatic kidney cancer patients with renal dysfunction 
Anti-cancer drugs  2011;22(8):794-800.
Multiple molecularly targeted agents (MTAs) have been approved for the management of metastatic renal cell carcinoma(mRCC). Sunitinib and M-TOR inhibitors (temsirolimus, everolimus) are primarily metabolized in the liver, while the metabolism of bevacizumab is unclear. There are limited data on the toxicity profile and efficacy of these agents in patients with renal impairment(RI). This is clinically relevant especially since about one third of mRCC patients have renal dysfunction.
The primary objective was to assess the safety and efficacy of targeted agents in mRCC patients with RI. Medical records of patients with mRCC at Wayne State University started on sunitinib, temsirolimus, everolimus or bevacizumab were reviewed. Patients with a calculated creatinine clearance(CrCl) of ≤60ml/min were deemed to have RI. Data on safety and efficacy of MTA therapy were collected and analyzed with respect to renal function.
RI was observed in 33% of our mRCC patients. The incidence of toxicities, responses, time to progression(TTP), and overall survival(OS) were not significantly different in patients with RI compared to patients with normal renal function. Patients with RI had larger median increases in blood pressure with sunitinib and bevacizumab, increased incidence of thyroid dysfunction with sunitinib, and increased incidence of rash and dose interruptions with m-TOR inhibitors, than did patients with normal renal function.
RI was commonly observed in our mRCC patients. MTAs are well tolerated and efficacy appears to be maintained in patients with RI. Vigilant monitoring of hypertension would be recommended for pts receiving sunitinib and bevacizumab.
PMCID: PMC3149855  PMID: 21799472
renal dysfunction; kidney cancer; sunitinib; temsirolimus; bevacizumab; everolimus
12.  Improving Conventional or Low Dose Metronomic Chemotherapy with Targeted Antiangiogenic Drugs 
One of the most significant developments in medical oncology practice has been the approval of various antiangiogenic drugs for the treatment of a number of different malignancies. These drugs include bevacizumab (Avastin®), the anti-VEGF monoclonal antibody. Thus far, bevacizumab appears to induce clinical benefit in patients who have advanced metastatic disease only or primarily when it is combined with conventional chemotherapy. The reasons for the chemo-enhancing effects of bevacizumab are unknown, and this is a subject that we have been actively studying along with additional ways that antiangiogenic drugs may be combined with chemotherapy. In this respect, we have focused much of our effort on metronomic low dose chemotherapy. We have been studying the hypothesis that some chemotherapy drugs at maximum tolerated doses or other cytotoxic- like drugs such as acute "vascular disrupting agents" (VDAs) can cause an acute mobilization of proangiogenic cells from the bone marrow which home to and colonize the treated tumors, thus accelerating their recovery. These cells include endothelial progenitor cells. This systemic process can be largely blocked by a targeted antiangiogenic drug, e.g. anti-VEGFR-2 antibodies. In addition, metronomic chemotherapy, i.e., close regular administration of chemotherapy drugs at low non-toxic doses with no breaks, over prolonged periods of time not only prevents the acute CEP bone marrow response, but can even target the cells. This potential antiangiogenic effect of metronomic chemotherapy can also be boosted by combination with a targeted antiangiogenic agent. Treatment combinations of metronomic chemotherapy and an antiangiogenic drug have moved into phase II clinical trial testing with particularly encouraging results thus far reported in metastatic breast and recurrent ovarian cancer. Oral chemotherapy drugs such as cyclophosphamide (CTX), methotrexate are the main chemotherapeutics used for such trials. Oral 5-FU prodrugs such as UFT would also appear to be highly suitable based on long term adjuvant therapy studies in patients. Recent preclinical results using metronomic cyclophosphamide and metronomic UFT in models of advanced metastatic breast cancer suggest that this type of combination might be particularly promising for metronomic chemotherapy in this indication, particularly when combined with a targeted antiangiogenic drug.
PMCID: PMC2739367  PMID: 19746237
Tumor angiogenesis; Antiangiogenic therapy; Metastasis; Breast cancer; Endothelial progenitor cells; VEGF; Vascular disrupting agents; Cyclophosphamide; UFT
13.  Nanodrug delivery in reversing multidrug resistance in cancer cells 
Different mechanisms in cancer cells become resistant to one or more chemotherapeutics is known as multidrug resistance (MDR) which hinders chemotherapy efficacy. Potential factors for MDR includes enhanced drug detoxification, decreased drug uptake, increased intracellular nucleophiles levels, enhanced repair of drug induced DNA damage, overexpression of drug transporter such as P-glycoprotein(P-gp), multidrug resistance-associated proteins (MRP1, MRP2), and breast cancer resistance protein (BCRP). Currently nanoassemblies such as polymeric/solid lipid/inorganic/metal nanoparticles, quantum dots, dendrimers, liposomes, micelles has emerged as an innovative, effective, and promising platforms for treatment of drug resistant cancer cells. Nanocarriers have potential to improve drug therapeutic index, ability for multifunctionality, divert ABC-transporter mediated drug efflux mechanism and selective targeting to tumor cells, cancer stem cells, tumor initiating cells, or cancer microenvironment. Selective nanocarrier targeting to tumor overcomes dose-limiting side effects, lack of selectivity, tissue toxicity, limited drug access to tumor tissues, high drug doses, and emergence of multiple drug resistance with conventional or combination chemotherapy. Current review highlights various nanodrug delivery systems to overcome mechanism of MDR by neutralizing, evading, or exploiting the drug efflux pumps and those independent of drug efflux pump mechanism by silencing Bcl-2 and HIF1α gene expressions by siRNA and miRNA, modulating ceramide levels and targeting NF-κB. “Theragnostics” combining a cytotoxic agent, targeting moiety, chemosensitizing agent, and diagnostic imaging aid are highlighted as effective and innovative systems for tumor localization and overcoming MDR. Physical approaches such as combination of drug with thermal/ultrasound/photodynamic therapies to overcome MDR are focused. The review focuses on newer drug delivery systems developed to overcome MDR in cancer cell.
PMCID: PMC4090910  PMID: 25071577
tumor microenvironment; drug efflux pumps; multidrug resistance; nanodrug delivery systems; theragnostic
14.  Dasatinib synergizes with both cytotoxic and signal transduction inhibitors in heterogeneous breast cancer cell lines - lessons for design of combination targeted therapy 
Cancer letters  2012;320(1):104-110.
Molecularly targeted therapies have emerged as the leading theme in cancer therapeutics. Multi-cytotoxic drug regimens have been highly successful, yet many studies in targeted therapeutics have centered on a single agent. We investigated whether the Src/Abl kinase inhibitor dasatinib displays synergy with other agents in molecularly heterogeneous breast cancer cell lines. MCF-7, SKBR-3, and MDA-MB-231 display different signaling and gene signatures profiles due to expression of the estrogen receptor, ErbB2, or neither. Cell proliferation was measured following treatment with dasatinib ± cytotoxic (paclitaxel, ixabepilone) or molecularly targeted agents (tamoxifen, rapamycin, sorafenib, pan PI3K inhibitor LY294002, and MEK/ERK inhibitor U0126). Dose-responses for single or combination drugs were calculated and analyzed by the Chou-Talalay method. The drugs with the greatest level of synergy with dasatinib were rapamycin, ixabepilone, and sorafenib, for the MDA-MB-231, MCF-7, and SK-BR-3 cell lines respectively. However, dasatinib synergized with both cytotoxic and molecularly targeted agents in all three molecularly heterogeneous breast cancer cell lines. These results suggest that effectiveness of rationally designed therapies may not entirely rest on precise identification of gene signatures or molecular profiling. Since a systems analysis that reveals emergent properties cannot be easily performed for each cancer case, multi-drug regimens in the near future will still involve empirical design.
PMCID: PMC3470854  PMID: 22306341
15.  A Combined Experimental and Mathematical Approach for Molecular-based Optimization of Irinotecan Circadian Delivery 
PLoS Computational Biology  2011;7(9):e1002143.
Circadian timing largely modifies efficacy and toxicity of many anticancer drugs. Recent findings suggest that optimal circadian delivery patterns depend on the patient genetic background. We present here a combined experimental and mathematical approach for the design of chronomodulated administration schedules tailored to the patient molecular profile. As a proof of concept we optimized exposure of Caco-2 colon cancer cells to irinotecan (CPT11), a cytotoxic drug approved for the treatment of colorectal cancer. CPT11 was bioactivated into SN38 and its efflux was mediated by ATP-Binding-Cassette (ABC) transporters in Caco-2 cells. After cell synchronization with a serum shock defining Circadian Time (CT) 0, circadian rhythms with a period of 26 h 50 (SD 63 min) were observed in the mRNA expression of clock genes REV-ERBα, PER2, BMAL1, the drug target topoisomerase 1 (TOP1), the activation enzyme carboxylesterase 2 (CES2), the deactivation enzyme UDP-glucuronosyltransferase 1, polypeptide A1 (UGT1A1), and efflux transporters ABCB1, ABCC1, ABCC2 and ABCG2. DNA-bound TOP1 protein amount in presence of CPT11, a marker of the drug PD, also displayed circadian variations. A mathematical model of CPT11 molecular pharmacokinetics-pharmacodynamics (PK-PD) was designed and fitted to experimental data. It predicted that CPT11 bioactivation was the main determinant of CPT11 PD circadian rhythm. We then adopted the therapeutics strategy of maximizing efficacy in non-synchronized cells, considered as cancer cells, under a constraint of maximum toxicity in synchronized cells, representing healthy ones. We considered exposure schemes in the form of an initial concentration of CPT11 given at a particular CT, over a duration ranging from 1 to 27 h. For any dose of CPT11, optimal exposure durations varied from 3h40 to 7h10. Optimal schemes started between CT2h10 and CT2h30, a time interval corresponding to 1h30 to 1h50 before the nadir of CPT11 bioactivation rhythm in healthy cells.
Author Summary
Treatment timing within the 24-h timescale, that is, circadian (circa, about; dies, day) timing, can change by several fold the tolerability and antitumor efficacy of anticancer agents both in experimental models and in cancer patients. Chronotherapeutics aims at improving the tolerability and/or the efficacy of medications through the administration of treatments according to biological rhythms. Recent findings highlight the need of individualizing circadian delivery schedules according to the patient genetic background. In order to address this issue, we propose a combined experimental and mathematical approach in which molecular mathematical models are fitted to experimental measurements of critical biological variables in the studied experimental model or patient. Optimization procedures are then applied to the calibrated mathematical model for the design of theoretically optimal circadian delivery patterns. As a first proof of concept we focused on the anticancer drug irinotecan. A mathematical model of the drug molecular PK-PD was built and fitted to experimental data in Caco-2 colon cancer cells. Numerical algorithms were then applied to theoretically optimize the chronomodulated exposure of Caco-2 cells to irinotecan.
PMCID: PMC3169519  PMID: 21931543
16.  Novel Epigenetic Target Therapy for Prostate Cancer: A Preclinical Study 
PLoS ONE  2014;9(5):e98101.
Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2′-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours.
PMCID: PMC4031137  PMID: 24851905
17.  An Integrated Disease/Pharmacokinetic/Pharmacodynamic Model Suggests Improved Interleukin-21 Regimens Validated Prospectively for Mouse Solid Cancers 
PLoS Computational Biology  2011;7(9):e1002206.
Interleukin (IL)-21 is an attractive antitumor agent with potent immunomodulatory functions. Yet thus far, the cytokine has yielded only partial responses in solid cancer patients, and conditions for beneficial IL-21 immunotherapy remain elusive. The current work aims to identify clinically-relevant IL-21 regimens with enhanced efficacy, based on mathematical modeling of long-term antitumor responses. For this purpose, pharmacokinetic (PK) and pharmacodynamic (PD) data were acquired from a preclinical study applying systemic IL-21 therapy in murine solid cancers. We developed an integrated disease/PK/PD model for the IL-21 anticancer response, and calibrated it using selected “training” data. The accuracy of the model was verified retrospectively under diverse IL-21 treatment settings, by comparing its predictions to independent “validation” data in melanoma and renal cell carcinoma-challenged mice (R2>0.90). Simulations of the verified model surfaced important therapeutic insights: (1) Fractionating the standard daily regimen (50 µg/dose) into a twice daily schedule (25 µg/dose) is advantageous, yielding a significantly lower tumor mass (45% decrease); (2) A low-dose (12 µg/day) regimen exerts a response similar to that obtained under the 50 µg/day treatment, suggestive of an equally efficacious dose with potentially reduced toxicity. Subsequent experiments in melanoma-bearing mice corroborated both of these predictions with high precision (R2>0.89), thus validating the model also prospectively in vivo. Thus, the confirmed PK/PD model rationalizes IL-21 therapy, and pinpoints improved clinically-feasible treatment schedules. Our analysis demonstrates the value of employing mathematical modeling and in silico-guided design of solid tumor immunotherapy in the clinic.
Author Summary
Among the many potential drugs explored within the scope of cancer immunotherapy are selected cytokines which possess promising immune-boosting properties. Yet, the natural involvement of these proteins in multiple, often contradicting biological processes can complicate their use in the clinic. The cytokine interleukin (IL)-21 is no exception: while its strength as an anticancer agent has been established in several animal studies, response rates in melanoma and renal cell carcinoma patients remain low. To help guide the design of effective IL-21 therapy, we have developed a mathematical model that bridges between the complex biology of IL-21 and its optimal clinical use. Our model integrates data from preclinical studies under diverse IL-21 treatment settings, and was validated by extensive experiments in tumor-bearing mice. Model simulations predicted that beneficial, clinically practical IL-21 therapy should be composed of low-dose schedules, and/or schedules in which several partial doses are administered rather than a single complete dose. These findings were subsequently confirmed in mice with melanoma. Thus, future testing of these strategies in solid cancer patients can be a promising starting point for improving IL-21 therapy. Our model can thus provide a computational platform for rationalizing IL-21 regimens and streamlining its clinical development.
PMCID: PMC3182868  PMID: 22022259
18.  A tumor cord model for Doxorubicin delivery and dose optimization in solid tumors 
Doxorubicin is a common anticancer agent used in the treatment of a number of neoplasms, with the lifetime dose limited due to the potential for cardiotoxocity. This has motivated efforts to develop optimal dosage regimes that maximize anti-tumor activity while minimizing cardiac toxicity, which is correlated with peak plasma concentration. Doxorubicin is characterized by poor penetration from tumoral vessels into the tumor mass, due to the highly irregular tumor vasculature. I model the delivery of a soluble drug from the vasculature to a solid tumor using a tumor cord model and examine the penetration of doxorubicin under different dosage regimes and tumor microenvironments.
A coupled ODE-PDE model is employed where drug is transported from the vasculature into a tumor cord domain according to the principle of solute transport. Within the tumor cord, extracellular drug diffuses and saturable pharmacokinetics govern uptake and efflux by cancer cells. Cancer cell death is also determined as a function of peak intracellular drug concentration.
The model predicts that transport to the tumor cord from the vasculature is dominated by diffusive transport of free drug during the initial plasma drug distribution phase. I characterize the effect of all parameters describing the tumor microenvironment on drug delivery, and large intercapillary distance is predicted to be a major barrier to drug delivery. Comparing continuous drug infusion with bolus injection shows that the optimum infusion time depends upon the drug dose, with bolus injection best for low-dose therapy but short infusions better for high doses. Simulations of multiple treatments suggest that additional treatments have similar efficacy in terms of cell mortality, but drug penetration is limited. Moreover, fractionating a single large dose into several smaller doses slightly improves anti-tumor efficacy.
Drug infusion time has a significant effect on the spatial profile of cell mortality within tumor cord systems. Therefore, extending infusion times (up to 2 hours) and fractionating large doses are two strategies that may preserve or increase anti-tumor activity and reduce cardiotoxicity by decreasing peak plasma concentration. However, even under optimal conditions, doxorubicin may have limited delivery into advanced solid tumors.
PMCID: PMC2736154  PMID: 19664243
19.  Rationally designed treatment for metastatic colorectal cancer: Current drug development strategies 
World Journal of Gastroenterology : WJG  2014;20(30):10288-10295.
The therapeutic landscape of metastatic colorectal cancer (mCRC) has changed substantially with the emergence of new molecularly targeted agents (MTA) used as single agents or alongside standard chemotherapy. The use of these MTAs extended the overall survival of patients with mCRC to a level that current chemotherapeutics alone could not achieve. In addition, improvement in surgical techniques and ablation modalities offer cure to a limited subset of patients with mCRC and MTAs have been found to have a significant role here too, as they aid resectability. However, for the majority of patients, mCRC remains an invariably incurable disease necessitating continued courses of combined treatment modalities. During the course of these treatments, either cytotoxic or biological, cancer cells maintain their ability to acquire mitogenic mutations which render them resistant to treatment. Key challenges remain to identify appropriate subsets of patients who will most likely benefit from these new MTAs and effectively select these based on validated biomarkers. Moreover, better knowledge of the biology of colorectal cancer and the mechanisms via which it bypasses blockade of known signalling pathways will help us design better and more rational sequencing of these treatments, so that we can maximise the survivorship of mCRC patients. This review outlines treatment strategies for known molecular alterations with new MTAs and highlights some promising strategies.
PMCID: PMC4130836  PMID: 25132745
Colorectal cancer; Molecularly targeted therapies; Drug development
20.  Evaluation of rodent-only toxicology for early clinical trials with novel cancer therapeutics 
British Journal of Cancer  1999;81(5):760-768.
Preclinical toxicology studies are performed prior to phase I trials with novel cancer therapeutics to identify a safe clinical starting dose and potential human toxicities. The primary aim of this study was to evaluate the ability of rodent-only toxicology studies to identify a safe phase I trial starting dose. In addition, the ability of murine studies to predict the quantitative and qualitative human toxicology of cancer therapeutics was studied. Data for 25 cancer drugs were collated for which the preclinical and clinical routes and schedules of administration were either the same (22/25), or closely matched. The maximum tolerated dose/dose lethal to 10% of mice (MTD/LD10) was identified for 24 drugs, and in patients the maximum administered dose (MAD) was associated with dose-limiting toxicity (DLT) in initial clinical trials with 20 compounds. In addition, for 13 agents, the toxicity of the drug at one-tenth the mouse MTD/LD10 was also investigated in rats, following repeated administration (20 doses). A phase I trial starting dose of one-tenth the mouse MTD/LD10 (mg m–2) was, or would have been, safe for all 25 compounds. With the exception of nausea and vomiting, which cannot be assessed in rodents, other common DLTs were accurately predicted by the murine studies (i.e. 7/7 haematological and 3/3 neurological DLTs). For two of the 13 drugs studied in rats, repeated administration of one-tenth the mouse MTD/LD10 was toxic, leading to a reduction in the phase I trial starting dose; however, one-tenth the mouse MTD/LD10 was subsequently tolerated in patients. For the 20 drugs where clinical DLT was reached, the median ratio of the human MAD to the mouse MTD/LD10 was 2.6 (range 0.2–16) and the median ratio of the clinical starting dose to the MAD was 35 (range 2.3–160). In contrast, in 13 subsequent phase I trials with 11 of the initial 25 drugs, the median ratio of the clinical starting dose to the MAD was 2.8 (range 1.6–56), emphasizing the value of early clinical data in rapidly defining the dose range for therapeutic studies. For all 25 drugs studied, rodent-only toxicology provided a safe and rapid means of identifying the phase I trial starting dose and predicting commonly encountered DLTs. This study has shown that the routine use of a non-rodent species in preclinical toxicology studies prior to initial clinical trials with cancer therapeutics is not necessary. © 1999 Cancer Research Campaign
PMCID: PMC2374299  PMID: 10555743
phase I trials; preclinical toxicology; starting dose
21.  Pterostilbene Acts through Metastasis-Associated Protein 1 to Inhibit Tumor Growth, Progression and Metastasis in Prostate Cancer 
PLoS ONE  2013;8(3):e57542.
The development of natural product agents with targeted strategies holds promise for enhanced anticancer therapy with reduced drug-associated side effects. Resveratrol found in red wine, has anticancer activity in various tumor types. We reported earlier on a new molecular target of resveratrol, the metastasis-associated protein 1 (MTA1), which is a part of nucleosome remodeling and deacetylation (NuRD) co-repressor complex that mediates gene silencing. We identified resveratrol as a regulator of MTA1/NuRD complex and re-activator of p53 acetylation in prostate cancer (PCa). In the current study, we addressed whether resveratrol analogues also possess the ability to inhibit MTA1 and to reverse p53 deacetylation. We demonstrated that pterostilbene (PTER), found in blueberries, had greater increase in MTA1-mediated p53 acetylation, confirming superior potency over resveratrol as dietary epigenetic agent. In orthotopic PCa xenografts, resveratrol and PTER significantly inhibited tumor growth, progression, local invasion and spontaneous metastasis. Furthermore, MTA1-knockdown sensitized cells to these agents resulting in additional reduction of tumor progression and metastasis. The reduction was dependent on MTA1 signaling showing increased p53 acetylation, higher apoptotic index and less angiogenesis in vivo in all xenografts treated with the compounds, and particularly with PTER. Altogether, our results indicate MTA1 as a major contributor in prostate tumor malignant progression, and support the use of strategies targeting MTA1. Our strong pre-clinical data indicate PTER as a potent, selective and pharmacologically safe natural product that may be tested in advanced PCa.
PMCID: PMC3586048  PMID: 23469203
22.  Phase 1/1b Study of Lonafarnib and Temozolomide in Patients With Recurrent or Temozolomide Refractory Glioblastoma 
Cancer  2013;119(15):2747-2753.
Lonafarnib is an oral selective farnesyltransferase inhibitor, a class of drugs which have shown activity in preclinical glioma models. Temozolomide (TMZ) is an alkylating agent that is the first-line chemotherapy for glioblastoma.
The current study combined the cytotoxic agent TMZ with the cytostatic agent lonafarnib for patients with recurrent glioblastoma to establish a maximum tolerated dose (MTD) of the combination and its preliminary efficacy. Three dose cohorts of lonafarnib were studied in the phase 1 component of the trial (100 mg twice daily [bid], 150 mg bid, and 200 bid) with dose-dense schedule of TMZ (150 mg/m2 daily) administered in an alternating weekly schedule. After establishing the MTD of lonafarnib, a subsequent expansion phase 1b was undertaken to evaluate efficacy, primarily measured by 6-month progression-free survival (PFS-6).
Fifteen patients were enrolled into the phase 1 component and 20 patients into the phase 1b component. The MTD of lonafarnib in combination with TMZ was 200 mg bid. Among the patients enrolled into the study, 34 were eligible for 6-month progression evaluation and 35 patients were evaluable for time-to-progression analysis. The PFS-6 rate was 38% (95% confidence interval [CI] = 22%, 56%) and the median PFS was 3.9 months (95% CI = 2.5, 8.4). The median disease-specific survival was 13.7 months (95% CI = 8.9, 22.1). Hematologic toxicities, particularly lymphopenia, were the most common grade 3 and 4 adverse events. There were no treatment-related deaths.
These results demonstrate that TMZ can be safely combined with a farnesyltransferase inhibitor and that this regimen is active, although the current study cannot determine the relative contributions of the 2 agents or the contribution of the novel administration schedule.
PMCID: PMC4001735  PMID: 23633392
glioblastoma; recurrent; lonafarnib; temozolomide; farnesyltransferase inhibitor
23.  Dose-dense chemotherapy improves mechanisms of antitumor immune response 
Cancer research  2012;73(1):119-127.
Dose-dense (DD) regimens of combination chemotherapy may produce superior clinical outcomes, but the basis for these effects are not completely clear. In this study, we assessed whether a DD combinatorial regimen of low-dose cisplatin and paclitaxel produces superior immune-mediated efficacy when compared to a maximum-tolerated dose (MTD) regimen, in treating platinum-resistant ovarian cancer as modeled in mice. Immune responses generated by the DD regimen were identified with regard to the immune cell subset responsible for the antitumor effects observed. The DD regimen was less toxic to the immune system, reduced immunosuppression by the tumor microenvironment, and triggered recruitment of macrophages and tumor-specific CD8+ T cell responses to tumors (as determined by IL-2 and IFN-γ secretion). In this model, we found that the DD regimen exerted greater therapeutic effects than the MTD regimen, justifying its further clinical investigation. Fourteen patients with platinum-resistant relapse of ovarian cancer received DD chemotherapy consisting of weekly carboplatin (AUC2) and paclitaxel (60-80 mg/m2) as the third or fourth-line treatment. Serum was collected over the course of treatment and serial IFN-γ and IL-2 levels were used to determine CD8+ T cell activation. Of the 4 patients with disease control, 3 had serum levels of IL-2 and IFN-γ associated with cytotoxic CD8+ T cell activity. The therapeutic effect of the DD chemotherapy relied on the preservation of the immune system and the treatment-mediated promotion of tumor-specific immunity, especially the antitumor CD8+ T cell response. Since the DD regimen controlled drug-resistant disease through a novel immune mechanism, it may offer a fine strategy for salvage treatment.
PMCID: PMC3537885  PMID: 23108141
chemotherapy; dose dense; antitumor immunity; drug-resistance; ovarian cancer
24.  Dose escalation of accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine and carboplatin chemotherapy in unresectable stage III non-small-cell lung cancer: a phase I trial 
Accelerated hypofractionated radiotherapy can shorten total treatment time and overcome the accelerated repopulation of tumour cells during radiotherapy. This therapeutic approach has demonstrated good efficacy in the treatment of locally advanced non-small-cell lung cancer (NSCLC). However, the optimal fractionation scheme remains uncertain. The purpose of this phase I trial was to explore the maximum tolerated dose (MTD) of accelerated hypofractionated three-dimensional conformal radiotherapy (3-DCRT) (at 3 Gy/fraction) administered in combination with concurrent vinorelbine (NVB) and carboplatin (CBP) chemotherapy for unresectable stage III NSCLC.
Previously untreated cases of unresectable stage III NSCLC received accelerated hypofractionated 3-DCRT, delivered at 3 Gy per fraction, once daily, with five fractions per week. The starting dose was 66 Gy and an increment of 3 Gy was utilized. Higher doses continued to be tested in patient groups until the emergence of dose-limiting toxicity (DLT). The MTD was regarded as the dose that was one step below the dose at which DLT occurred. Patients received at least one cycle of a concurrent two-drug chemotherapy regimen of NVB and CBP.
A total of 13 patients were enrolled and progressed through three dose escalation groups: 66 Gy, 69 Gy, and 72 Gy. No treatment-related deaths occurred. The major adverse events included radiation oesophagitis, radiation pneumonitis, and neutropenia. Nausea, fatigue, and anorexia were commonly observed, although the magnitude of these events was typically relatively minor. Among the entire group, four instances of DLT were observed, including two cases of grade 3 radiation oesophagitis, one case of grade 3 radiation pneumonitis, and one case of grade 4 neutropenia. All of these cases of DLT occurred in the 72 Gy group. Therefore, 72 Gy was designated as the DLT dose level, and the lower dose of 69 Gy was regarded as the MTD.
For unresectable stage III NSCLC 69 Gy (at 3 Gy/fraction) was the MTD of accelerated hypofractionated 3-DCRT administered in combination with concurrent NVB and CBP chemotherapy. The toxicity of this chemoradiotherapy regimen could be tolerated. A phase II trial is recommended to further evaluate the efficacy and safety of this regimen.
PMCID: PMC3765388  PMID: 23957889
Accelerated hypofractionated radiotherapy; Three-dimensional conformal radiotherapy; Non-small-cell lung cancer; Concurrent chemoradiotherapy; Maximum tolerated dose; Vinorelbine; Carboplatin
25.  Phase I study of continuous MKC-1 in patients with advanced or metastatic solid malignancies using the modified Time-to-Event Continual Reassessment Method (TITE-CRM) dose escalation design 
Investigational New Drugs  2011;30(3):1039-1045.
MKC-1 is an oral cell-cycle inhibitor with broad antitumor activity in preclinical models. Clinical studies demonstrated modest antitumor activity using intermittent dosing schedule, however additional preclinical data suggested continuous dosing could be efficacious with additional effects against the mTor/AKT pathway. The primary objectives were to determine the maximum tolerated dose (MTD) and response of continuous MKC-1. Secondary objectives included characterizing the dose limiting toxicities (DLTs) and pharmacokinetics (PK).
Patients with solid malignancies were eligible, if they had measurable disease, ECOG PS ≤1, and adequate organ function. Exclusions included brain metastases and inability to receive oral drug. MKC-1 was dosed twice daily, continuously in 28-day cycles. Other medications were eliminated if there were possible drug interactions. Doses were assigned using a TITE-CRM algorithm following enrollment of the first 3 pts. Disease response was assessed every 8 weeks
Between 5/08-9/09, 24 patients enrolled (15 M/9 F, median 58 years, range 44-77). Patients 1-3 received 120 mg/d of MKC-1; patients 4-24 were dosed per the TITE-CRM algorithm: 150 mg [n=1], 180 [2], 200 [1], 230 [1], 260 [5], 290 [6], 320 [5]. The median time on drug was 8 weeks (range 4-28). The only DLT occurred at 320 mg (grade 3 fatigue). Stable disease occurred at 150 mg/d (28 weeks; RCC) and 320 mg/d (16 weeks; breast, parotid). Escalation halted at 320 mg/d. Day 28 pharmacokinetics indicated absorption and active metabolites.
Continuous MKC-1 was well-tolerated; there were no RECIST responses, although clinical benefit occurred in 3/24 pts. Dose escalation stopped at 320 mg/d, and this is the MTD as defined by the CRM dose escalation algorithm; this cumulative dose/cycle exceeds that determined from intermittent dosing studies. A TITE-CRM allowed for rapid dose escalation and was able to account for late toxicities with continuous dosing via a modified algorithm.
PMCID: PMC3139017  PMID: 21225315
MKC-1; TITE-CRM; Solid malignancy; Novel dose escalation designs

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