The isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes mutate frequently in gliomas, and it has become increasingly apparent that IDH mutation status accounts for much of the prognostic information previously rendered by histological grading. Most glioblastomas (90–95%) are IDH-wild type and most lower-grade diffuse gliomas (80%) are IDH-mutant. We examine here how IDH mutation status interacts with treatments known to influence survival (surgery, chemotherapy, and radiotherapy) in patients with gliomas, and the impact of IDH mutations on patients’ survival after such treatments. IDH mutations are associated with more complete surgical resection of enhancing disease, and with a better response to radiotherapy. Additionally, there is increasing clinical evidence that, in certain contexts, IDH mutations predict chemotherapeutic sensitivity. Mutations in IDH and other genes are beginning to drive decisions on therapy for diffuse gliomas, and will likely allow tailoring of treatment by molecular profile in the future.
IDH mutation; Chemotherapy; Gliomas; Surgery; Radiotherapy
Melanoma patients develop resistance to most therapies, including chemo- and targeted-therapy drugs. Single-agent therapies are ineffective due to the heterogeneous nature of tumors comprising several subpopulations. Treatment of melanoma with immune-based therapies such as anti-cytotoxic T-lymphocyte activation-4 and anti-programmed death-1 antibodies has shown modest but long-lasting responses. Unfortunately, only subsets of melanoma patients respond to antibody-based therapies. Heterogeneity in lymphocyte infiltration and low frequency of anti-melanoma-reactive T-cells in tumor lesions are partly responsible for a lack of response to antibody-based therapies. Both antibodies have same biological function but they bind to different ligands at various phases of T-cell activity. Thus, combination therapy of antibodies has shown superior response rates than single-agent therapy. However, toxicity is a cause of concern in these therapies. Future identification of therapy-response biomarkers, mobilization of tumor-reactive T-cell infiltration using cancer vaccines, or non-specific targeted-therapy drugs will minimize toxicity levels and provide long-term remissions in melanoma patients.
antibody therapy; anti-CTLA-4; anti-PD-1; immune-checkpoint inhibitors; Melanoma
Several studies have found associations between aggressive prostate cancer and having a vasectomy. However, findings from two very recent meta-analyses have found that this is not the case. Therefore, the data is mixed. Herein, we detail the controversy between vasectomy and prostate cancer risk, particularly aggressive prostate cancer, by shedding some light on the molecular pathways, potential risk factors, and suggested links for those considering vasectomy and medical professionals who perform it. We conclude by supporting the American Urological Association’s position that, while patients should be informed of potential risks of vasectomy, there is no established link between prostate cancer and choosing to have a vasectomy.
prostate; cancer; vasectomy; risk; epidemiology
Glioblastoma is a common aggressive primary malignant brain tumor, and is nearly universal in progression and mortality after initial treatment. Re-irradiation presents a promising treatment option for progressive disease, both palliating symptoms and potentially extending survival. Highly conformal radiation techniques such as stereotactic radiosurgery and hypofractionated radiosurgery are effective short courses of treatment that allow delivery of high doses of therapeutic radiation with steep dose gradients to protect normal tissue. Patients with higher performance status, younger age, and longer interval between primary treatment and progression represent the best candidates for re-irradiation. Multiple studies are also underway involving combinations of radiation and systemic therapy to bend the survival curve and improve the therapeutic index. In the multimodal treatment of recurrent high-grade glioma, the use of surgery, radiation, and systemic therapy should be highly individualized. Here we comprehensively review radiation therapy and techniques, along with discussion of combination treatment and novel strategies.
Radiation therapy; high grade glioma; glioblastoma; stereotactic radiosurgery
Worldwide, the incidence of melanoma continues to rise. Although not the most common cutaneous malignancy, it is the most lethal. Until recently, while other oncologic patients benefited from the nuances of targeted therapy, those afflicted with melanoma lacked that option. In 2011, the US FDA approved an oral agent that targets the BRAF oncogene. As this information is promising, it is essential that other populations (in addition to Caucasians) are examined, in order to further comprehend the biology of melanoma. Recent studies profiling various ethnicities, including Asians, have provided novel data with respect to the molecular characterization (c-KIT, BRAF, NRAS) of melanoma. It is hopeful that the management of melanoma will be universally applicable to all ethnic groups.
BRAF; c-KIT; ethnic personalization; melanoma; molecular profiling; NRAS; targeted therapy; vemurafenib
Non-Hodgkin lymphoma (NHL) comprises numerous biologically and clinically heterogeneous subtypes, with limited data examining risk factors for these distinct disease entities. Many limitations exist when studying lymphoma epidemiology, therefore until recently little was known regarding the etiology of NHL subtypes. This review highlights the results of recent pooled analyses examining risk factors for NHL subtypes. We outline heterogeneity and commonality among risk factors for NHL subtypes, with proposed subtype-specific as well as shared etiologic mechanisms. In addition, we describe how the study of lymphoma epidemiology may translate into prevention or therapeutic targeting as we continue to explore the complexities of lifestyle and genetic factors that impact lymphomagenesis.
non-Hodgkin lymphoma; epidemiology; risk factors
In preclinical studies protein kinase C (PKC) enzymes have been implicated in regulating many aspects of pancreatic cancer development and progression. However, clinical phase I or phase II trials with compounds targeting classical PKC isoforms were not successful. Recent studies implicate that mainly atypical and novel PKC enzymes regulate oncogenic signaling pathways in pancreatic cancer. Members of these two subgroups converge signaling induced by mutant Kras, growth factors and inflammatory cytokines. Different approaches for development of inhibitors for aPKC and nPKC have been described; and new compounds include allosteric inhibitors and inhibitors that block ATP binding.
PKC; protein kinase C; inhibitor; pancreatic cancer; therapy
Recent technical advances have enabled for the first time, reliable in vitro culture of prostate cancer samples as prostate cancer organoids. This breakthrough provides the significant possibility of high throughput drug screening covering the spectrum of prostate cancer phenotypes seen clinically. These advances will enable precision medicine to become a reality, allowing patient samples to be screened for effective therapeutics ex vivo, with tailoring of treatments specific to that individual. This will hopefully lead to enhanced clinical outcomes, avoid morbidity due to ineffective therapies and improve the quality of life in men with advanced prostate cancer.
organoids; prostate cancer; in vitro; therapeutics; precision medicine; 3D culture
Urothelial carcinoma of the bladder comprises a spectrum of illnesses ranging from nonmuscle-invasive to muscle-invasive to advanced/metastatic disease. Each of these clinical states is characterized by a unique pathogenesis, prognosis and approach to treatment. However, given the heterogeneity of urothelial carcinoma, differences in biology and outcomes exist not only among these clinical states but also within each state. Personalized medicine, also commonly referred to as individualized or stratified medicine, offers the potential to optimize treatment for a given patient, based on the ability to accurately predict prognosis, response to treatment and tolerability of treatment. This review will discuss recent efforts, current challenges and future opportunities, for the personalized management of urothelial carcinoma.
biomarker; bladder cancer; chemotherapy; neoadjuvant therapy; personalized medicine; urothelial carcinoma
All-trans retinoic acid (ATRA) is one of the most successful examples of differentiation agents and histone deacetylase inhibitors, such as tributyrin (TB), are known for their antitumor activity and potentiating action of drugs such as ATRA. Nanostructured lipid carriers (NLC) represent a promising alternative to the encapsulation of lipophilic drugs such as ATRA. This study aimed to develop, characterize, and evaluate the cytotoxicity of ATRA-TB-loaded nanostructured lipid carriers (NLC) for cancer treatment.
The influence of in situ formation of an ion pairing between ATRA and a lipophilic amine (benethamine; BNT) on the characteristics of NLC (size, zeta potential, encapsulation efficiency) was evaluated. Tributyrin (TB), a butyric acid donor, was used as a component of the lipid matrix. In vitro activity on cell viability and distribution of cell cycle phases were evaluated for MCF-7, MDA-MB-231, HL-60, and Jurkat cell lines.
The presence of the amine significantly increased the encapsulation efficiency of ATRA in NLC. Inhibition of cell viability by TB-ATRA-loaded NLC was more pronounced than the free drug. Analysis of the distribution of cell cycle phases also showed increased activity for TB-ATRA-loaded NLC, with the clear effect of cell cycle arrest in G0/G1 phase transition. The presence of TB played an important role in the activity of the formulation.
Taken together, these findings suggest that TB-ATRA-loaded NLC represent a promising alternative to intravenous administration of ATRA in cancer treatment.
nanostructured lipid carriers; all-trans retinoic acid; tributyrin; histone deacetylase inhibitors; cancer; cytotoxicity
Clinical heterogeneity represents a great challenge for cancer therapeutics. Molecular classification of patients into different subtypes based on genetic or epigenetic characteristics has the potential to revolutionize the clinical care and mechanistic understanding of a wide spectrum of cancers, including endometrial carcinoma, the most common gynecological cancer affecting women.
Molecular subtyping; Endometrial carcinoma; CTNNB1 mutation; Wnt signaling pathway; Cancer therapeutics
The current classification system for breast cancer is based on expression of prognostic and predictive biomarkers. As an alternative, we propose a hypothesis-based ontological breast cancer classification modeled after the taxonomy of species in evolutionary biology. This approach uses normal breast epithelial cell types and differentiation lineages as the gold standard to classify tumors. We show that there are at least eleven previously undefined normal cell types in human breast epithelium and that each breast carcinoma is related to one of these normal cell types. We find that triple negative breast cancers do not have a ‘basal-like’ phenotype. Normal breast epithelial cells conform to four novel hormonal differentiation states and almost all human breast tumors duplicate one of these hormonal differentiation states which have significant survival differences. This ontological classification scheme provides actionable treatment strategies and provides an alternative approach for understanding tumor biology with wide-ranging implications for tumor taxonomy.
breast cancer diagnostics; Nurses’ Health Study; pathology; biomarkers; heterogeneity; -omics
Androgen deprivation therapy is the standard of care for patients with advanced hormone-sensitive prostate cancer. Despite an initial response, most patients progress to castration-resistant prostate cancer (CRPC). The realization that CRPC remains driven by androgen receptor (AR) signaling has formed the basis for a new generation of agents targeting the AR axis. Two of these agents, abiraterone acetate and enzalutamide, have been shown to prolong overall survival in patients with CRPC. Several other AR inhibitors are currently in development for the treatment of CRPC. The present article reviews ODM-201, a new-generation AR inhibitor with a unique molecular structure, in the treatment of CRPC. The design of an ongoing Phase III trial (ARAMIS) of ODM-201 in men with non-metastatic CRPC is also discussed, at a disease stage for which there is currently no approved treatment.
androgen receptor inhibitors; castration resistant; efficacy; metastatic; non-metastatic; ODM-201; pharmacodynamics; pharmacokinetics; prostate cancer; tolerability
Microbeam radiation therapy (MRT) is a promising preclinical modality for cancer treatment, with remarkable preferential tumoricidal effects, that is, tumor eradication without damaging normal tissue functions. Significant lifespan extension has been demonstrated in brain tumor-bearing small animals treated with MRT. So far, MRT experiments can only be performed in a few synchrotron facilities around the world. Limited access to MRT facilities prevents this enormously promising radiotherapy technology from reaching the broader biomedical research community and hinders its potential clinical translation. We recently demonstrated, for the first time, the feasibility of generating microbeam radiation in a laboratory environment using a carbon nanotube x-ray source array and performed initial small animal studies with various brain tumor models. This new nanotechnology-enabled microbeam delivery method, although still in its infancy, has shown promise for achieving comparable therapeutic effects to synchrotron MRT and has offered a potential pathway for clinical translation.
brain tumor; carbon nanotube; glioblastoma multiforme; image guidance; microbeam radiation therapy; temozolomide; U87MG glioma; x-ray; γ-H2AX
High-density lipoproteins (HDLs) are a diverse group of natural nanoparticles that are most well-known for their role in cholesterol transport. However, HDLs have diverse functions that provide significant opportunities for cancer therapy. Presented is a focused review of the ways that synthetic versions of HDL have been used as targeted therapies for cancer, and as vehicles for the delivery of diverse therapeutic cargo to cancer cells. As such, synthetic HDLs are likely to play a central role in the development of next generation cancer therapies.
High-density lipoprotein; cholesterol; cancer, drug delivery; nucleic acids; scavenger receptor
After initial response to androgen receptor targeting drugs abiraterone or enzalutamide, most patients develop progressive disease and therefore, castration resistant prostate cancer (CRPC) remains a terminal disease. Multiple mechanisms underlying acquired resistance have been postulated. Intratumoral androgen synthesis may resume after abiraterone treatment. A point mutation in the ligand binding domain of androgen receptor may confer resistance to enzalutamide. Emergence of androgen receptor splice variants lacking the ligand binding domain may mediate resistance to abiraterone and enzalutamide. Steroid receptors such as glucocorticoid receptor may substitute for androgen receptor. Drugs with novel mechanisms of action or combination therapy, along with biomarkers for patient selection, may be needed to improve the therapy of CRPC.
Prostate cancer; androgen receptor; abiraterone; enzalutamide; acquired drug resistance; androgen receptor splice variants; intratumoral androgen synthesis; glucocorticoid receptor
Valproic acid is an inhibitor of class I histone deacetylases. Epigenetic therapies in cancer have been focus of a keen interest and HDAC inhibitors in particular have been approved for certain types of hematologic malignancies. Valproic acid is an attractive candidate for cancer therapy due to its mechanism of action, its low cost and generally good clinical tolerability. In the following editorial we will review its role as monotherapy for cancer, its place in combination epigenetic therapy, and its role as chemosensitizer, immunomodulator and cancer preventative agent.
There is an emerging interest in understanding mechanisms of response and resistance to next-generation hormonal therapies: abiraterone and enzalutamide. While many explanations for resistance to these agents have been postulated, the importance of androgen receptor splice variants is gaining momentum. Androgen receptor (AR) splice variants are constitutively active isoforms of the AR that lack the ligand-binding domain yet retain their transcriptional activity in a ligand-independent fashion. Of these, AR variant-7 may be the most important, and has been implicated in primary resistance to abiraterone and enzalutamide in men with advanced prostate cancer. In this editorial, the clinical relevance of AR splice variant-7 (AR-V7) will be reviewed within the context of AR-directed therapies, and next steps for the analytical and clinical validation of this potential biomarker will be proposed.
abiraterone; androgen receptor; AR-V7; enzalutamide; splice variant
The unmatched efficacy of microtubule-targeting agents (MTAs) as chemotherapeutics was once assumed to originate from their impact on mitotic processes; however, this misconception is being eroded by amassing data that MTAs instead target interphase functions in patients’ tumors. What remains murky is how MTAs target malignant cells over non-malignant ones if proliferation rates do not distinguish them. In many instances, malignant cells are actually more ‘primed’ for apoptosis than non-malignant ones. Nevertheless, even if most cells within the tumor are more apoptosis-susceptible than those in healthy tissues, there likely exist small subpopulations of apoptosis-resistant clones that engender incomplete responses to MTAs and relapse. Therefore, intratumor heterogeneity in terms of proximity to the apoptotic threshold must be better understood to facilitate the design of chemotherapeutic regimens, which may benefit from including drugs like BH3 mimetics that help in lowering the apoptotic threshold of tumor cells within these chemoresistant subpopulations.
apoptotic threshold; chemoresistance; intratumor heterogeneity; mitochondrial priming; tubulin inhibitors
The contemporary clinical landscape of gastrointestinal stromal tumor (GIST) has evolved rapidly over the past several years. Widely used treatment guidelines – from the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network – have recently been updated and represent the most up-to-date, comprehensive tools guiding the optimal management of GIST. In these, and in other published guidelines, close alignment among recommendations now exists for many of the clinical issues relevant to GIST management – surgery, use of the tyrosine kinase inhibitors imatinib and sunitinib and the role of pre- and post-operative imatinib, among others. This trend towards a global consensus in the treatment of GIST is the result of a relatively large amount of new data across the spectrum of its management. However, for some clinical considerations, recommendations still partially deviate. This review examines clinical recommendations and opinions on the management of GIST in the context of the latest data in the field and with an eye towards a multidisciplinary approach including surgical oncology, medical oncology, pathology and diagnostic radiology. Points of consensus are highlighted. Expert opinion is presented on management areas where no scientific evidence or firm recommendations currently exist; lingering and unresolved questions or issues are included. Within this framework, we present an evaluation of current global guidelines on the following areas in GIST management: surgery in the metastatic setting; neoadjuvant therapy; adjuvant therapy; mutational analysis; maintenance tyrosine kinase inhibitor therapy; and radiological imaging in GIST. A summary of consensus across these guidelines based on clinical trial data is juxtaposed with expert opinion where gaps in data still remain.
adjuvant; European Society of Medical Oncology; gastrointestinal stromal tumor; guidelines; imatinib; KIT; National Comprehensive Cancer Network; nilotinib; PDGFR-α; sarcoma; sunitinib; tyrosine kinase inhibitor
HPV-positive oropharyngeal squamous cell carcinoma (HPV-OSCC) is associated with oral sexual behaviors. The sharp rise in incidence of HPV-OSCC in the USA has been attributed to changes in sexual norms over the past five decades, with lower age at sexual debut and higher numbers of sexual partners per individual. In addition, variations in HPV-OSCC prevalence by race, age cohort and gender may be attributable to differences in oral sexual behaviors among these groups. Oral HPV infection is the putative precursor to HPV-OSCC. Risk factors for oral HPV incidence, prevalence, clearance and persistence are crucial to understanding how, and in whom, oral HPV infection progresses to malignancy. Future investigation should focus on elucidating the natural history of oral HPV infection persistence and malignant transformation, developing effective screening tools and exploring opportunities for prevention such as vaccination and public health education.
head and neck neoplasms; health education; human papillomavirus; human papillomavirus vaccines; oral sex; oropharyngeal neoplasms; sexual behavior; sexually transmitted diseases
Emerging evidence suggests that when cancer cells hijack normal stem cell properties, they acquire the ability to invade, metastasize to distant sites, and evade therapy. Thus, eliminating cancer cells with stem cell properties, or cancer stem cells, is of prime importance for the successful treatment of cancer, regardless of the tissue of origin. Previous efforts to target cancer stem cells, however, have been largely unsuccessful. Recent studies led to the discovery of a novel role for the high mobility group A1 protein as a master regulator in both cancer stem cells and normal embryonic stem cells. Here, we present exciting new work unveiling the HMGA1 as a promising target for therapies directed at eradicating cancer stem cells.
High mobility group A1 protein; HMGA1; cancer stem cells; epithelial-mesenchymal transition; embryonic stem cells; chromatin remodeling proteins
Chronic lymphocytic leukemia (CLL) exhibits a highly variable natural history, but the addition of genomic risk stratification to traditional clinical staging systems has begun to explain the heterogeneous clinical course. Overall response to treatment has significantly improved over the past three decades, and for the first time, a survival benefit has been demonstrated with the use of monoclonal antibodies in combination with cytotoxic chemotherapy. Newer therapeutic strategies have abrogated the adverse prognosis associated with some higher-risk features, but other genetic subgroups remain at high risk for rapid disease progression and early mortality. Patients at advanced age or with significant co morbidity constitute a large proportion of the CLL population and present unique clinical challenges. This review will discuss the evolution of contemporary therapeutic approaches to the initial treatment of CLL and highlight the ways in which risk-adapted therapeutic strategies are improving clinical outcomes.
chronic lymphocytic leukemia; risk stratification; chemo immunotherapy; fludarabine; cyclophosphamide; rituximab; chlorambucil; bendamustine; alemtuzumab; pentostatin
Assessing the tumor response of liver cancer lesions after intraarterial therapies is of major clinical interest. Over the last two decades, tumor response criteria have come a long way from purely size-based, anatomic methods such as the Response Evaluation Criteria in Solid Tumors towards more functional, enhancement- and diffusion-based parameters with a strong emphasis on MRI as the ultimate imaging modality. However, the relatively low reproducibility of those one- and 2D techniques (modified Response Evaluation Criteria in Solid Tumors and the European Association for the Study of the Liver criteria) provided the rationale for the development of new, 3D quantitative assessment techniques. This review will summarize and compare the existing methodologies used for 3D quantitative tumor analysis and provide an overview of the published clinical evidence for the benefits of 3D quantitative tumor response assessment techniques.
3D; ADC; intraarterial therapy; liver cancer; MRI; qEASL; quantitative imaging; RECIST; tumor response