The development of tyrosine kinase inhibitors (TKIs) for the treatment of chronic myelogenous leukemia (CML) was based on the discovery that CML stem and progenitor cells overexpress the abnormal fusion protein kinase BCR-ABL. The prototype TKI, imatinib, selectively inhibits BCR-ABL, as well as several other kinases, including DDR, KIT, PDGFR, and CSF-1R. Although the management of CML improved dramatically with the introduction of imatinib, not all patients benefit from treatment because of resistance or intolerance. Consequently, research efforts have focused on developing more potent TKIs with the ability to circumvent imatinib resistance. Nilotinib, a second-generation oral TKI, was rationally designed based on the crystal structure of imatinib to be highly active against a wide range of imatinib-resistant BCR-ABL mutants and is approved for the treatment of newly diagnosed or imatinib-resistant or -intolerant CML, and has shown superiority over imatinib in first-line in newly diagnosed CML. Furthermore, the activity of nilotinib against KIT and PDGFRα has led to its evaluation in advanced gastrointestinal stromal tumors (GIST). The purpose of this review is to describe the development of nilotinib, providing a structural explanation for the differential activity of nilotinib and imatinib in GIST. Activity of nilotinib against KIT and PDGFR and emerging evidence of differences in cellular uptake between nilotinib and imatinib are discussed.
Nilotinib; AMN107; fusion proteins; BCR-ABL; stem cell factor receptor; receptors; platelet-derived growth factor; gastrointestinal stromal tumors; drug resistance
Imatinib is the standard of care for patients with advanced metastatic gastrointestinal stromal tumors (GIST), and is also approved for adjuvant treatment in patients at substantial risk of relapse. Studies have shown that maximizing benefit from imatinib depends on long-term administration at recommended doses. Pharmacokinetic (PK) and pharmacodynamic factors, adherence, and drug–drug interactions can affect exposure to imatinib and impact clinical outcomes. This article reviews the relevance of these factors to imatinib’s clinical activity and response in the context of what has been demonstrated in chronic myelogenous leukemia (CML), and in light of new data correlating imatinib exposure to response in patients with GIST. Because of the wide inter-patient variability in drug exposure with imatinib in both CML and GIST, blood level testing (BLT) may play a role in investigating instances of suboptimal response, unusually severe toxicities, drug–drug interactions, and suspected non-adherence. Published clinical data in CML and in GIST were considered, including data from a PK substudy of the B2222 trial correlating imatinib blood levels with clinical responses in patients with GIST. Imatinib trough plasma levels <1100 ng/mL were associated with lower rates of objective response and faster development of progressive disease in patients with GIST. These findings have been supported by other analyses correlating free imatinib (unbound) levels with response. These results suggest a future application for imatinib BLT in predicting and optimizing therapeutic response. Nevertheless, early estimates of threshold imatinib blood levels must be confirmed prospectively in future studies and elaborated for different patient subgroups.
Gastrointestinal neoplasms; Sarcoma; Tyrosine kinase inhibitors; Pharmacokinetics; Pharmacodynamics; Drug monitoring; Dose-response relationship
Altered cysteine dioxygenase 1 (CDO1) gene expression has been observed in several cancers but has not yet been investigated in liposarcomas. The aim of this study was to evaluate CDO1 expression in a cohort of liposarcomas and to determine its association with clinicopathological features. Existing microarray data indicated variable CDO1 expression in liposarcoma subtypes. CDO1 mRNA from a larger cohort of liposarcomas was quantified by real time-PCR, and CDO1 protein expression was determined by immunohistochemistry (IHC) in more than 300 tumor specimens. Well-differentiated liposarcomas (WDLSs) had significantly higher CDO1 gene expression and protein levels than dedifferentiated liposarcomas (DDLSs) (P < 0.001). Location of the tumor was not predictive of the expression level of CDO1 mRNA in any histological subtype of liposarcoma. Recurrent tumors did not show any difference in CDO1 expression when compared to primary tumors. CDO1 expression was upregulated as human mesenchymal stem cells (hMSCs) undergo differentiation into mature adipocytes. Our results suggest that CDO1 is a marker of liposarcoma progression and adipogenic differentiation.
liposarcoma; cysteine dioxygenase 1; adipocyte differentiation
Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR) complex 1, is approved for the treatment of metastatic renal cell carcinoma (RCC). Bryostatin-1 inhibits protein kinase C, a downstream effector of mTOR complex 2. We observed antitumor effects with the combination of temsirolimus and bryostatin-1 in RCC cell lines.
Four cohorts of patients received weekly bryostatin-1 (20 μg/m2) with temsirolimus (10, 15, 25, or 37.5 mg) in 28-day cycles.
Thirty patients received a total of 138 cycles across four dose levels. Twenty-five patients had RCC (17 clear cell, 7 papillary, and 1 unclassified). Two sarcoma patients with prior cytotoxic therapy experienced dose-limiting toxicity at 15 mg of temsirolimus (grade 3 neutropenia and grade 3 hypophosphatemia). Subsequently, patients with prior cytotoxic therapy were excluded. Two additional dose-limiting toxicities were noted with 37.5 mg of temsirolimus (grade 3 neutropenia and grade 3 creatinine elevation). Consequently, the maximum tolerated dose was defined as temsirolimus at 25 mg and bryostatin-1 at 20 μg/m2 every 28 days. Of the 25 RCC patients, 3 patients had partial responses that lasted for 14 months, 28 months, and ≥80 months, respectively. Partial responses were seen in both clear cell and papillary histology.
This combination of 37.5 mg of temsirolimus with 20 μg/m2 of bryostatin-1 was reasonably safe and well tolerated. Durable responses were observed in 3 of 25 patients with RCC.
Approximately 15% of gastrointestinal stromal tumors (GISTs) in adults and 85% in children lack mutations in KIT and PDGFRA and are known as wild type GISTs. Wild type GISTs from adults and children express high levels of insulin-like growth factor 1 receptor (IGF1R) and exhibit stable genomes compared to mutant GISTs. Pediatric wild type GISTs, GISTs from the multi-tumor Carney-Stratakis syndrome and the Carney triad share other clinico-pathological properties (e.g. early-onset, multifocal GISTs with epitheliod cell morphology) suggesting a common etiology. Carney-Stratakis is an inherited association of GIST and paragangliomas caused by germline mutations in succinate dehydrogenase (SDH) genes. The connection between defective cellular respiration and GIST pathology has been strengthened by the utilization of SDHB immunohistochemistry to identify SDH deficiency in pediatric GISTs, syndromic GISTs, and some adult wild type GISTs. SDHB and IGF1R expression was examined in 12 wild type and 12 mutant GIST cases. Wild type GISTs were screened for coding-region alterations in SDH genes and for chromosomal aberrations using genome-wide SNP and MIP arrays. SDHB-deficiency, identified in 11/12 wild type GIST cases, was tightly associated with over-expression of IGF1R protein and transcript. Biallelic inactivation of the SDHA gene was a surprisingly frequent event, identified in 5/11 SDHB-negative cases, generally due to germline point mutations accompanied by somatic SDHA allelic losses. As a novel finding, inactivation of the SDHC gene from a combination of a heterozygous coding-region mutation and hyper-methylation of the wild type allele was found in one SDHB-negative case.
Purpose The IGF-1R signaling pathway has been implicated in multiple cancers as important for cell survival, proliferation, invasion and metastasis. BIIB022 is a non-glycosylated human IgG4 monoclonal antibody (mAb) with specificity for IGF-1R. Unlike other anti-IGF1R antibodies, BIIB022 has no effector functions. Additionally, inhibition is via an allosteric rather than competitive mechanism, which further differentiates this antibody from others. We sought to determine the safety and tolerability of BIIB022 and determine the pharmacokinetic (PK) and pharmacodynamic (PD) profile of this antibody. Methods A multi-institutional phase I study evaluated the safety of escalating doses of BIIB022 given IV q3wk until progression or unacceptable toxicity in patients with advanced solid tumors. Five sequential BIIB022 dose cohorts were evaluated using a standard 3 + 3 dose-escalation design (1.5, 5. 10, 20, 30 mg/kg); 10 additional patients were treated at the recommended phase 2 dose. Results 34 patients were treated. Toxicities were manageable and mostly low grade; grade 3–4 hyperglycemia was not observed. No RECIST responses were observed, although three patients had metabolic responses associated with prolonged stable disease. The PK of BIIB022 was nearly linear in the dose range from 10 to 30 mg/kg, with some nonlinearity at lower doses (1.5–5.0 mg/kg), likely due to target-mediated drug disposition of BIIB022 at low serum concentrations. PD analyses showed decrease in IGF-1R levels on leucocytes, with stable serum values of IGF-1 and IGF-2. Conclusions BIIB022 can be safely given at 30 mg/kg IV every 3 weeks with preliminary evidence of biological activity in selected patients.
IGF-1R; Antibody; Phase I; Sarcoma; FDG-PET
To date, only two agents, imatinib and sunitinib, have shown clinical benefit in patients with gastrointestinal stromal tumours (GISTs), but almost all metastatic GISTs eventually develop resistance to these agents, resulting in fatal disease progression. This phase 3 trial assessed efficacy and safety of regorafenib in patients with metastatic and/or unresectable GIST progressing after failure of at least imatinib and sunitinib.
Patients were randomised 2:1 to receive either regorafenib 160 mg orally daily or placebo, plus best supportive care in both arms, for the first 3 weeks of each 4-week cycle. The primary endpoint was progression-free survival (PFS). Upon disease progression, patients on placebo could cross over to regorafenib. Secondary endpoints included overall survival (OS), objective response rate, disease control rate (DCR: rate of durable stable disease lasting for ≥12 weeks plus complete or partial responses), and safety. This trial is registered at ClinicalTrials.gov (NCT01271712).
From January to August 2011, 240 patients were screened at 57 centres in 17 countries, and 199 patients were randomised to receive regorafenib (n=133) or matching placebo (n=66). Median PFS per independent blinded central review was 4·8 months and 0·9 months, respectively (hazard ratio [HR] 0·27, 95% confidence interval [CI] 0·19–0·39; p<0·0001). Following progression, 56/66 patients (84·8%) on placebo crossed over to regorafenib, resulting in no significant difference in OS between study arms (HR 0·77, 95% CI 0·42–1·41; p=0·199). A best response of partial response or stable disease was observed in 101/133 patients (75·9%) on regorafenib and 23/66 patients (34·8%) on placebo. DCR was 52·6% (70/133 patients) and 9·1% (6/66 patients), respectively. Drug-related adverse events were reported in 130 (98·5%) of 132 regorafenib patients and 45 (68·2%) of 66 placebo patients. The most common grade ≥3 regorafenib-related adverse events were hypertension (31/132, 23·5%), hand–foot skin reaction (26/132, 19·7%), and diarrhoea (7/132, 5·3%).
Regorafenib significantly improved PFS and DCR, compared with placebo, in patients with advanced GIST progressing after failure of at least imatinib and sunitinib.
Hypertension is a toxicity of antiangiogenic therapies and a possible biomarker that identifies patients with superior cancer outcomes. Understanding its mechanism will aid in treatment and could lead to the development of other biomarkers for predicting toxicity and anticancer efficacy. Recent evidence implicates nitric oxide (NO) suppression and endothelin-1 (ET-1) stimulation as potential mechanisms leading to antiangiogenic therapy-induced hypertension. The aim of this study was to evaluate the effects of regorafenib, a novel broad-spectrum kinase inhibitor with activity against multiple targets, including vascular endothelial growth factor receptor 2 inhibition, on NO and ET-1 levels.
Regorafenib was administered to 32 subjects with gastrointestinal stromal tumor on a 3-week-on, 1-week-off basis. Plasma levels of NO and ET-1 were measured at baseline, 2, 4, and 6 weeks of therapy. Data analysis was by Wilcoxon rank-sum and paired t-tests.
Twenty subjects (63%) developed regorafenib-induced hypertension. Two weeks after starting regorafenib therapy, plasma ET-1 levels increased (25% increase, P < 0.05) and NO was suppressed (20% decrease, P < 0.05). These normalized after 1-week washout but ET-1 rose again by 30% (P < 0.05) and NO fell by 50% (P < 0.05) after restarting regorafenib.
These findings indicate that regorafenib induces a coordinated and reversible suppression of NO and stimulation of ET-1. Whether NO and ET-1 might predict therapeutic efficacy in these patients requires further study.
American Journal of Hypertension, advance online publication 12 July 2012. doi:10.1038/ajh.2012.97
antiangiogenic therapy; blood pressure; endothelin-1; hypertension; nitric oxide
Head/neck sarcomas are rare, accounting for about 1% of head/neck malignancies and 5% of sarcomas. Outcomes have historically been worse in this group, due to anatomic constraints leading to difficulty in completely excising tumors, with high rates of local recurrence. We retrospectively analyzed cases of head/neck soft tissue sarcomas (STS) and osteogenic sarcomas managed in a multi-disciplinary setting at Fox Chase Cancer Center from 1999–2009 to describe clinicopathologic characteristics, treatment, outcomes, and prognostic factors for disease control and survival. Thirty patients with STS and seven patients with osteogenic sarcoma were identified. Most STS were high grade (23) and almost all were localized at presentation (28). Common histologies were synovial cell (6), rhabdomyosarcoma (5), angiosarcoma (4), liposarcoma (4) and leiomyosarcoma (3). The type of primary therapy and disease outcomes were analyzed. Cox proportional hazards regression analysis was performed to identify predictors of disease-free survival (DFS) and overall survival (OS). The HR and 95% CI for Cox model and median DFS/OS analyzed by Kaplan-Meier curves were calculated.
head and neck sarcomas; soft tissue sarcomas; osteogenic sarcomas
Little is known about the outcome of patients with microscopically positive (R1) resections for primary gastro-intestinal stromal tumors (GISTs), because existing retrospective series are comprised of small numbers of patients. The objective of this study was to analyze factors associated with R1 resection and assess the risk of recurrence with and without imatinib.
Operative and pathology reports for 819 patients undergoing resection of primary GIST from North American ACOSOG Z9000 and Z9001 clinical trials at 230 institutions testing adjuvant imatinib after resection of primary GIST were reviewed. Patient, tumor, operative characteristics, factors associated with R1 resections, and disease status were analyzed.
Seventy two (8.8%) patients had an R1 resection and were followed for a median of 49 months. Factors associated with R1 resection included tumor size (≥10cm), location (rectum) and tumor rupture. The risk of disease recurrence in R1 patients was driven largely by the presence of tumor rupture. There was no significant difference in recurrence free survival for patients undergoing an R1 vs. R0 resection of GIST with (HR=1.095, 95% CI: 0.66, 1.82, p=0.73) or without (HR=1.51, 95% CI: 0.76, 2.99, p=0.24) adjuvant imatinib.
Approximately 9% of 819 GIST patients had an R1 resection. Significant factors associated with R1 resection include tumor size ≥10cm, location and rupture. The difference in recurrence free survival with or without imatinib therapy in those undergoing an R1 vs. R0 resection was not statistically significant at a median follow-up of 4 years.
Metastatic GI stromal tumor (GIST) is a life-threatening disease with no therapy of proven efficacy after failure of imatinib and sunitinib. Regorafenib is a structurally unique inhibitor of multiple cancer-associated kinases, including KIT and platelet-derived growth factor receptor (PDGFR), with broad-spectrum anticancer activity in preclinical and early-phase trials. Because KIT and PDGFR-α remain drivers of GIST after resistance to imatinib and sunitinib, we performed a multicenter single-stage phase II trial of regorafenib in patients with advanced GIST after failure of at least imatinib and sunitinib.
Patients and Methods
Patients received regorafenib orally, 160 mg daily, on days 1 to 21 of a 28-day cycle. Disease assessment was performed every two cycles per RECIST 1.1. Primary end point was clinical benefit rate (CBR), defined as objective responses (ie, complete or partial response [PR] as well as stable disease [SD] ≥ 16 weeks). Serial tumor biopsies were obtained from consenting patients whenever possible.
From February to December 2010, 34 patients were enrolled at four US centers. As of July 28, 2011, 33 patients had received at least two cycles of regorafenib (range, two to 17 cycles). CBR was 79% (95% CI, 61% to 91%). Four patients achieved PR, and 22 exhibited SD ≥ 16 weeks. Median progression-free survival was 10.0 months. The most common grade 3 toxicities were hypertension and hand-foot-skin reaction.
Regorafenib has significant activity in patients with advanced GIST after failure of both imatinib and sunitinib. A phase III trial of regorafenib versus placebo is ongoing to define more fully the safety and efficacy of regorafenib in this setting.
Although imatinib mesylate (IM) has transformed the treatment of gastrointestinal stromal tumors (GIST), many patients experience primary/secondary drug resistance. In a previous study, we identified a gene signature, consisting mainly of Kruppel-associated box (KRAB) domain containing zinc finger (ZNF) transcriptional repressors that predict short-term response to IM. To determine if these genes have functional significance, a siRNA library targeting these genes was constructed and applied to GIST cells in vitro. These screens identified seventeen “IM sensitizing genes” in GIST cells (sensitization index (SI) <0.85 ratio of drug/vehicle) with a false discovery rate (FDR) <15%, including twelve ZNF genes, the majority of which are located within the HSA19p12–13.1 locus. These genes were shown to be highly specific to IM and another tyrosine kinase inhibitor (TKI), sunitinib, in GIST cells. In order to determine mechanistically how these ZNFs might be modulating response to IM, RNAi approaches were used to individually silence genes within the predictive signature in GIST cells and expression profiling was performed. Knockdown of the 14 IM-sensitizing genes (10 ZNFs) universally led to downregulation of six genes, including TGFb3, periostin, and NEDD9. These studies implicate a role of KRAB-ZNFs in modulating response to TKIs in GIST.
Gastrointestinal stromal tumors (GISTs) in adults are generally driven by somatic gain-of-function mutations in KIT or PDGFRA, and biological therapies targeted to these receptor tyrosine kinases comprise part of the treatment regimen for metastatic and inoperable GISTs. A minority (10–15%) of GISTs in adults, along with ∼85% of pediatric GISTs, lacks oncogenic mutations in KIT and PDGFRA. Not surprisingly these wild type (WT) GISTs respond poorly to kinase inhibitor therapy. A subset of WT GISTs shares a set of distinguishing clinical and pathological features, and a flurry of recent reports has convincingly demonstrated shared molecular characteristics. These GISTs have a distinct transcriptional profile including over-expression of the insulin-like growth factor-1 receptor, and exhibit deficiency in the succinate dehydrogenase (SDH) enzyme complex. The latter is often but not always linked to bi-allelic inactivation of SDH subunit genes, particularly SDHA. This review will summarize the molecular, pathological, and clinical connections that link this group of SDH-deficient neoplasms, and offer a view toward understanding the underlying biology of the disease and the therapeutic challenges implicit to this biology.
gastrointestinal stromal tumor; wild type; succinate dehydrogenase; insulin-like growth factor receptor; review
Toll-like receptors are potent activators of the innate immune system and generate signals leading to the initiation of the adaptive immune response that can be utilized for therapeutic purposes. We tested the hypothesis that combined treatment with a toll-like receptor agonist and an anti-tumor monoclonal antibody is effective and induces host-protective anti-tumor immunity. C57BL/6 human mutated HER2 (hmHER2) transgenic mice that constitutively express kinase-deficient human HER2 under control of the CMV promoter were established. These mice demonstrate immunological tolerance to D5-HER2, a syngeneic human HER2-expressing melanoma cell line. This human HER2 tolerant model offers the potential to serve as a preclinical model to test both antibody therapy and the immunization potential of human HER2 targeted therapeutics. Here we show that E6020, a toll like receptor-4 (TLR4) agonist effectively boosted the antitumor efficacy of the monoclonal antibody trastuzumab in immunodeficient C57BL/6 SCID mice as well as in C57BL/6 hmHER2 transgenic mice. E6020 and trastuzumab co-treatment resulted in significantly greater inhibition of tumor growth than was observed with either agent individually. Furthermore, mice treated with the combination of trastuzumab and the TLR4 agonist were protected against re-challenge with human HER2 transfected tumor cells in hmHER2 transgenic mouse strains. These findings suggest that combined treatment with trastuzumab and a TLR4 agonist not only promotes direct anti-tumor effects but also induces a host-protective human HER2-directed adaptive immune response indicative of a memory response. These data provide an immunological rationale for testing TLR4 agonists in combination with antibody therapy in patients with cancer.
toll like receptor 4 agonist; HER2; antibody therapy; transgenic mouse; antitumor immunity
Sarcomas are a heterogeneous group of solid tumors arising from either soft tissues or bone, accounting for approximately 1% of all cancers in adults. Management of these diseases has changed little over the past 10 years, with the exception of treatment of gastrointestinal stromal tumors. Reasons for this stagnation include multiple histologies commonly grouped together in clinical trials limiting the understanding of benefit of treatment and limited investigation of molecular targeted therapies. More recently, advances in molecular pathogenesis, the advent of novel and targeted therapeutics, and increasing collaborations between sarcoma investigators has helped move the field forward in the right direction. Here, we review the recent data on novel agents tested for the management of adult soft-tissue sarcomas, excluding gastrointestinal stromal tumors.
soft tissue sarcoma; clinical trials; trabectedin; palifosfamide; pazopanib
This multicenter randomized trial was designed to test whether melanoma-associated helper peptides augment CD8+ T-cell responses to a melanoma vaccine and whether cyclophosphamide (CY) pretreatment augments CD4+ or CD8+ T-cell responses to that vaccine.
Patients and Methods
In all, 167 eligible patients with resected stage IIB to IV melanoma were randomly assigned to four vaccination study arms. Patients were vaccinated with 12 class I major histocompatibility complex–restricted melanoma peptides (12MP) to stimulate CD8+ T cells and were randomly assigned to receive a tetanus helper peptide or a mixture of six melanoma-associated helper peptides (6MHP) to stimulate CD4+ T cells. Before vaccination, patients were also randomly assigned to receive CY pretreatment or not. T-cell responses were assessed by an ex vivo interferon gamma ELISpot assay. Clinical outcomes and toxicities were recorded.
Vaccination with 12MP plus tetanus induced CD8+ T-cell responses in 78% of patients and CD4+ T-cell responses to tetanus peptide in 93% of patients. Vaccination with 12MP plus 6MHP induced CD8+ responses in 19% of patients and CD4+ responses to 6MHP in 48% of patients. CY had no significant effect on T-cell responses. Overall 3-year survival was 79% (95% CI, 71% to 86%), with no significant differences (at this point) by study arm.
Melanoma-associated helper peptides paradoxically decreased CD8+ T-cell responses to a melanoma vaccine (P < .001), and CY pretreatment had no immunologic or clinical effect. Prior work showed immunologic and clinical activity of 6MHP alone. Possible explanations for negative effects on CD8 responses include modulation of homing receptor expression or induction of antigen-specific regulatory T cells.
Aurora A kinase is critical in assembly and function of the mitotic spindle. It is overexpressed in various tumor types and implicated in oncogenesis and tumor progression. This trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of MLN8054, a selective small-molecule inhibitor of Aurora A kinase.
In this first-in-human, dose-escalation study, MLN8054 was given orally for 7, 14, or 21 days followed by a 14-day treatment-free period. Escalating cohorts of 3–6 patients with advanced solid tumors were treated until DLT was seen in ≥2 patients in a cohort. Serial blood samples were collected for pharmacokinetics and skin biopsies were collected for pharmacodynamics.
Sixty-one patients received 5, 10, 20, 30 or 40 mg once daily for 7 days; 25, 35, 45 or 55 mg/day in four divided doses (QID) for 7 days; or 55, 60, 70 or 80 mg/day plus methylphenidate or modafinil with daytime doses (QID/M) for 7–21 days. DLTs of reversible grade 3 benzodiazepine-like effects defined the estimated MTD of 60 mg QID/M for 14 days. MLN8054 was absorbed rapidly, exposure was dose-proportional, and terminal half-life was 30-40 hours. Three patients had stable disease for >6 cycles.
MLN8054 dosing for up to 14 days of a 28-day cycle was feasible. Reversible somnolence was dose limiting and prevented achievement of plasma concentrations predicted necessary for target modulation. A recommended dose for investigation in phase 2 trials was not established. A second-generation Aurora A kinase inhibitor is in development.
MLN8054; Aurora A kinase; dose-limiting toxicity; pharmacokinetics; pharmacodynamics
Soft tissue sarcomas are a diverse set of fatal human tumors where few agents have demonstrable clinical efficacy, with the standard therapeutic combination of doxorubicin and ifosfamide showing only a 25–30% response rate in large multi-institutional trials. Although liposarcomas are the most common histological form of adult soft tissue sarcomas, research in this area is severely hampered by the lack of experimentally tractable in vitro model systems. To this end, here we describe a novel in vitro model for human pleomorphic liposarcoma. The cell line (LS2) is derived from a pleomorphic liposarcoma that utilizes the Alternative Lengthening of Telomeres (ALT) mechanism of telomere maintenance, which may be important in modulating the response of this tumor type to DNA damaging agents. We present detailed baseline molecular and genomic data, including genome wide copy number and transcriptome profiles, for this model compared to its parental tumor and a panel of liposarcomas covering multiple histologies. The model has retained essentially all of the detectable alterations in copy number that are seen in the parental tumor, and shows molecular karyotypic and expression profiles consistent with pleomorphic liposarcomas. We also demonstrate the utility of this model, together with two additional human liposarcoma cell lines, to investigate the relationship between topoisomerase 2A expression and the sensitivity of ALT-positive liposarcomas to doxorubicin. This model, together with its associated baseline data, provide a powerful new tool to develop treatments for this clinically poorly-tractable tumor, and to investigate the contribution that ALT makes to modulating sensitivity to doxorubicin.
Liposarcoma; Telomere maintenance mechanism; expression profile; molecular karyotype
Gastrointestinal stromal tumors are mesenchymal tumors of the gastrointestinal tract. They commonly metastasize within the abdominal cavity, particularly to the liver. Less commonly, metastases can be found in the lung or bone. This report describes the first two cases of metastasis to the left ventricle in patients with advanced gastrointestinal stromal tumor.
gastrointestinal stromal tumors; metastasis; ventricle; heart
Purpose of review
Gastrointestinal stromal tumors are the most common sarcoma of the gastrointestinal tract. A decade ago, the only therapy for gastrointestinal stromal tumors was surgery. Treatment paradigms changed with the discovery that gastrointestinal stromal tumor cells express KIT, a tyrosine kinase growth factor receptor, which is mutated in 85% of cases. Imatinib and sunitinib are tyrosine kinase inhibitors with activity against advanced gastrointestinal stromal tumors. This review will discuss the available data on the use of imatinib in the adjuvant setting and the role of imatinib and sunitinib in the neoadjuvant setting.
Retrospective series and prospective studies have demonstrated the benefit of adjuvant imatinib. Randomized data show improved recurrence free survival in patients receiving imatinib for 1 year postoperatively. Ongoing studies are further defining the length of adjuvant therapy. The neoadjuvant treatment decreases tumor size to allow for surgical resection with less morbidity. The imatinib neoadjuvant therapy in a prospective randomized study was safe with encouraging outcomes. This approach for palliating advanced disease also appears to be safe following imatinib, sunitinib, or other tyrosine kinase inhibitors therapy.
Treatment for gastrointestinal stromal tumors, formerly limited to surgery, now is a combination of surgery and tyrosine kinase inhibitors therapy. Combination therapy is safe and improves outcomes, particularly in the adjuvant setting.
adjuvant; gastrointestinal stromal tumors; imatinib; neoadjuvant; sunitinib
This study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of the intravenous pan-aurora kinase inhibitor PHA-739358, danusertib, in patients with advanced solid tumors.
In Part 1, patients received escalating doses of danusertib (24-h infusion every 14 days) without filgrastim (G-CSF). Febrile neutropenia was the dose-limiting toxicity without G-CSF. Further dose escalation was performed in part 2 with G-CSF. Blood samples were collected for danusertib pharmacokinetics and pharmacodynamics. Skin biopsies were collected to assess histone H3 phosphorylation (pH3).
Fifty-six patients were treated, 40 in part 1 and 16 in part 2. Febrile neutropenia was the dose limiting toxicity in Part 1 without G-CSF. Most other adverse events were grade 1–2, occurring at doses ≥360 mg/m2 with similar incidence in parts 1 and 2. The MTD without G-CSF is 500 mg/m2. The recommended phase 2 dose (RP2D) in Part 2 with G-CSF is 750 mg/m2. Danusertib demonstrated dose-proportional pharmacokinetics in parts 1 and 2 with a median half-life of 18–26 hours. pH3 modulation in skin biopsies was observed at ≥500 mg/m2. One patient with refractory small cell lung cancer (1000 mg/m2 with G-CSF) had an objective response lasting 23 weeks. One patient with refractory ovarian cancer had 27% tumor regression and 30% CA125 decline.
Danusertib was well tolerated with target inhibition in skin at ≥500 mg/m2. Preliminary evidence of anti-tumor activity, including a PR and several occurrences of prolonged stable disease (SD), was seen across a variety of advanced refractory cancers. Phase II studies are ongoing.
Danusertib; PHA-739358; Aurora Kinase Inhibitor; phase I trial; solid tumors
Gastrointestinal stromal tumors (GISTs) generally harbor activating mutations in KIT or PDGFRA. Mutations in these receptor tyrosine kinases lead to dysregulation of downstream signaling pathways that contribute to GIST pathogenesis. GISTs with KIT or PDGFRA mutations also undergo secondary cytogenetic alterations that may indicate the involvement of additional genes important in tumor progression. Approximately 10–15% of adult and 85% of pediatric GISTs do not have mutations in KIT or in PDGFRA. Most mutant adult GISTs display large-scale genomic alterations, but little is know about the mutation-negative tumors. Using genome-wide DNA arrays, we investigated genomic imbalances in a set of 31 GISTs, including 10 KIT/PDGFRA mutation-negative tumors from 9 adults and 1 pediatric case and 21 mutant tumors. While all 21 mutant GISTs exhibited multiple copy number aberrations, notably losses, 8 of the 10 KIT/PDGFRA mutation-negative GISTs exhibited few or no genomic alterations. One KIT/PDGFRA mutation-negative tumor exhibiting numerous genomic changes was found to harbor an alternate activating mutation, in the serine-threonine kinase BRAF. The only other mutation-negative GIST with significant chromosomal imbalances was a recurrent metastatic tumor found to harbor a homozygous deletion in chromosome 9p. Similar findings in several KIT-mutant GISTs identified a minimal overlapping region of deletion of ~0.28 Mbp in 9p21.3 that includes only the CDKN2A/2B genes, which encode inhibitors of cell-cycle kinases. These results suggest that GISTs without activating kinase mutations, whether pediatric or adult, generally exhibit a much lower level of cytogenetic progression than that observed in mutant GISTs.
GISTs; KIT; PDGFRA; BRAF; imatinib mesylate; DNA copy number analysis
To study the safety, tolerability and pharmacokinetics (PK) of the selective tyrosine kinase inhibitor nilotinib as a single-agent or in combination with imatinib in patients with advanced imatinib-resistant gastrointestinal stromal tumors (GIST).
A Phase I intercohort dose-escalation trial was performed in patients who received either (1) single-agent nilotinib 400 mg bid or (2) escalating doses of nilotinib (200 mg qd, 400 mg qd, or 400 mg bid) plus imatinib 400 mg bid (10- and 14-hour interval daily), or (3) nilotinib 400 mg bid plus imatinib 400 mg qd. Safety, PK and tumor assessments were performed.
Oral clearance (CL/F) of nilotinib was similar across the combination groups (mean CL/F=19.1-25.6 L/h), and lower than in the single-agent cohort (mean CL/F=35.6 L/h). A linear relationship between nilotinib daily dose and peak concentration (Cmax) was observed in the combination cohorts. Observed adverse events (AEs) were mostly non-hematological. Frequently reported AEs were rash (40%), fatigue (38%), abdominal pain (36%) and nausea (36%). Severe AEs (grade 3 or 4) included abdominal pain (13%) and rash (9%), the latter mainly with the combination. Thirty-eight patients had stable disease and two patients achieved partial response with a median progression-free survival of 134 days for the entire group.
Nilotinib alone or in combination with imatinib was well tolerated overall and showed clinical activity in imatinib-resistant GIST patients. This Phase I trial identified single-agent nilotinib 400 mg bid or combined with imatinib 400 mg qd as possible Phase II doses for further evaluation.
nilotinib; imatinib; gastrointestinal stromal tumors (GIST); Phase I; pharmacokinetics (PK)
Despite initial efficacy of imatinib mesylate (IM) in most gastrointestinal stromal tumor (GIST) patients, many experience primary/secondary drug resistance. Therefore, clinical management of GIST may benefit from further molecular characterization of tumors before and after IM treatment.
As part of a recent Phase II Trial of neoadjuvant/adjuvant IM treatment for advanced primary and recurrent operable GISTs (RTOG-S0132), gene expression profiling using oligonucleotide microarrays was performed on tumor samples obtained before and after IM therapy. Patients were classified according to changes in tumor size after treatment based on CT scan measurements. Gene profiling data were evaluated with Statistical Analysis of Microarrays (SAM) to identify differentially expressed genes (in pre-treatment GIST samples).
Based on SAM (FDR=10%), thirty-eight genes were expressed at significantly lower levels in the pre-treatment biopsy samples from tumors that significantly responded to 8 to 12 weeks of IM, i.e., ≥25% tumor reduction. Eighteen of these genes encoded KRAB domain containing zinc finger (KRAB-ZNF) transcriptional repressors. Importantly, ten KRAB-ZNF genes mapped to a single locus on chromosome 19p, and a subset predicted likely response to IM-based therapy in a naïve panel of GISTs. Furthermore, we found that modifying expression of genes within this predictive signature can enhance the sensitivity of GIST cells to IM.
Using clinical pre-treatment biopsy samples from a prospective neoadjuvant phase II trial we have identified a gene signature that includes KRAB-ZNF 91 subfamily members that may be both predictive of and functionally associated with likely response to short term IM treatment.
GISTs; imatinib mesylate; microarray; KRAB-ZNF genes
The management of advanced GIST is increasingly complex due to imatinib refractory disease. Primary resistance to imatinib is uncommon, and most patients progress after development of additional genetic changes. This article reviews management strategies including surgical approaches, local modalities for progressive liver metastases, as well as novel therapeutic agents.
GIST; nilotinib; sorafenib; HSP-90 inhibitors; IGF-1R; tyrosine kinase inhibitors