Bromodomain inhibitors a decade later: a promise unfulfilled?

Over the last decade, bromodomain inhibitors have emerged as a promising class of anticancer drugs. However, the clinical progress of these agents has faced significant obstacles, which precluded their regulatory approval. This editorial will review the challenges and opportunities associated with the development of bromodomain inhibitors.

A phase Ib dose-escalation and expansion study of the oral MEK inhibitor pimasertib and PI3K/MTOR inhibitor voxtalisib in patients with advanced solid tumours.

BACKGROUND: This phase Ib study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of pimasertib (MSC1936369B), a MEK1/2 inhibitor, in combination with voxtalisib (SAR245409), a pan-PI3K and mTORC1/mTORC2 inhibitor, in patients with advanced solid tumours. METHODS: This study included a dose escalation and expansion in patients with select tumour types and alterations in the MAPK or PI3K pathways. A 3 + 3 design was used to determine MTD. Patients were evaluated for adverse events and tumour response. RESULTS: 146 patients were treated, including 63 in dose escalation and 83 in expansion. The MTD was pimasertib 90 mg and voxtalisib 70 mg daily. Based on the safety profile, the recommended phase 2 dose (RP2D) was pimasertib 60 mg and voxtalisib 70 mg. The most frequent treatment-emergent adverse events (TEAEs) were diarrhoea (75%), fatigue (57%), and nausea (50%). Responses included a complete response in one patient (1%), partial response in five (5%), and stable disease in 51 (46%). At the RP2D, 74 patients required dose interruption (73%), 20 required dose reduction (20%), and 26 discontinued treatment due to TEAEs (26%). CONCLUSIONS: The combination of pimasertib and voxtalisib showed poor long-term tolerability and limited anti-tumour activity in patients with advanced solid tumours.

Phase 1 safety, pharmacokinetic and pharmacodynamic study of the cyclin-dependent kinase inhibitor dinaciclib administered every three weeks in patients with advanced malignancies.

BACKGROUND: Dinaciclib is a potent inhibitor of cell cycle and transcriptional cyclin-dependent kinases. This Phase 1 study evaluated the safety, tolerability and pharmacokinetics of various dosing schedules of dinaciclib in advanced solid tumour patients and assessed pharmacodynamic and preliminary anti-tumour activity. METHODS: In part 1, patients were enrolled in escalating cohorts of 2-h infusions administered once every 3 weeks, utilising an accelerated titration design until a recommended phase 2 dose (RP2D) was defined. In part 2, 8- and 24-h infusions were evaluated. Pharmacokinetic parameters were determined for all schedules. Pharmacodynamic effects were assessed with an ex vivo stimulated lymphocyte proliferation assay performed in whole blood.Effects of dinaciclib on retinoblastoma (Rb) phosphorylation and other CDK targets were evaluated in skin and tumour biopsies. In addition to tumour size, metabolic response was evaluated by 18F-fluorodeoxyglucose-positron emission tomography. RESULTS: Sixty-one patients were enrolled to parts 1 and 2. The RP2Ds were 50, 7.4 and 10.4 mg m-2 as 2- 8- and 24-hour infusions, respectively. Dose-limiting toxicities included pancytopenia, neutropenic fever, elevated transaminases, hyperuricemia and hypotension. Pharmacokinetics demonstrated rapid distribution and a short plasma half-life. Dinaciclib suppressed proliferation of stimulated lymphocytes. In skin and tumour biopsies, dinaciclib reduced Rb phosphorylation at CDK2 phospho-sites and modulated expression of cyclin D1 and p53, suggestive of CDK9 inhibition. Although there were no RECIST responses, eight patients had prolonged stable disease and received between 6 and 30 cycles. Early metabolic responses occurred. CONCLUSIONS: Dinaciclib is tolerable at doses demonstrating target engagement in surrogate and tumour tissue.

Pharmacokinetic study of aldoxorubicin in patients with solid tumors.

Introduction Aldoxorubicin, a prodrug of doxorubicin, binds covalently to serum albumin in the bloodstream and accumulates in tumors. Aldoxorubicin can be administered at doses several-fold higher than doxorubicin can, without associated acute cardiotoxicity. Purpose This study fully evaluated the pharmacokinetic profile of aldoxorubicin (serum and urine). Methods Eighteen patients with advanced solid tumors received aldoxorubicin 230 or 350 mg/m(2) (equivalent in drug load to doxorubicin at doses of 170 or 260 mg/m(2), respectively) once every 21 days. Blood samples were taken in cycle 1 before aldoxorubicin infusion, and at 5, 15, 30, and 60 min, and at 2, 4, 8, 12, 16, 24, 48, and 72 h after infusion. Urine samples were taken in cycle 1 at 24, 48, and 72 h after infusion. Limited blood sampling was done in cycle 3, before aldoxorubicin infusion, and at 60 min and at 2, 4, and 8 h after infusion. Results The long mean half-life (20.1-21.1 h), narrow mean volume of distribution (3.96-4.08 L/m(2)), and slow mean clearance rate (0.136-0.152 L/h/m(2)) suggest that aldoxorubicin is stable in circulation and does not accumulate readily in body compartments outside of the bloodstream. Very little doxorubicin and its major metabolite doxorubicinol, which has been implicated in doxorubicin-associated cardiotoxicity, are excreted in urine. This might explain the lack of cardiotoxicity observed thus far with aldoxorubicin. Conclusions Our findings support dosing and administration schemas used in an ongoing phase 3 clinical study of aldoxorubicin in soft tissue sarcoma, and phase 2 clinical studies in small cell lung cancer, glioblastoma, and Kaposi's sarcoma.

Relative bioavailability of a prototype oral solution of the Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors.

OBJECTIVES: Alisertib (MLN8237) is an investigational, oral, small-molecule, selective inhibitor of Aurora A kinase. Phase I/II studies of powder-in-capsule (PIC) and enteric-coated tablet formulations of alisertib have determined the recommended phase II dose and have demonstrated anti-tumor activity. This phase I relative bioavailability study characterized the pharmacokinetics of a prototype oral solution (OS) of alisertib (developed for patients unable to swallow solid dosage forms) in reference to the PIC formulation in adult cancer patients. MATERIALS AND METHODS: A safety evaluation was undertaken first following a 3+3 design (OS starting dose, 15 mg). The relative bioavailability of alisertib OS vs. PIC was then evaluated following single dose administration of alisertib OS 25 mg and PIC 50 mg, using a 2-way crossover study design. RESULTS: The relative bioavailability (geometric mean dose-normalized AUCinf ratio) of alisertib OS vs. PIC formulation was 1.26 (90% confidence interval (CI): 1.09-1.47 (OS, n=17; PIC, n=18 evaluable patients)). These results support a distinguishable difference in bioavailability of alisertib between the two formulations (lower bound of 90% CI>1), with an estimated 26% higher total systemic exposure with alisertib OS vs. PIC. Alisertib absorption from OS was faster than from PIC, with a shorter median tmax (OS, 1 hour; PIC, 2 hours) and a geometric mean dose-normalized Cmax ratio (OS vs. PIC) of 1.90 (90% CI: 1.52 - 2.37). CONCLUSIONS: These findings inform the starting dose of alisertib OS to support further clinical evaluation of alisertib in patients unable to swallow solid dosage forms.

Phase I dose-escalation study of cabazitaxel administered in combination with cisplatin in patients with advanced solid tumors.

INTRODUCTION: Cabazitaxel is a second-generation taxane with in vivo activity against taxane-sensitive and -resistant tumor cell lines and tumor xenografts. Cabazitaxel/cisplatin have therapeutic synergism in tumor-bearing mice, providing a rationale for assessing this combination in patients with solid tumors. METHODS: The primary objectives of this study were to determine dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of a cabazitaxel/cisplatin combined regimen (Part 1) and to assess antitumor activity at the MTD (Part 2). Safety and pharmacokinetics (PK) were also examined. RESULTS: Twenty-five patients with advanced solid tumors were enrolled (10 in Part 1; 15 in Part 2). In Part 1, two dose levels were evaluated; the MTD for cabazitaxel/cisplatin (given Q3W) was 15/75 mg/m(2). DLTs occurring during Cycle 1 at the maximum administered dose (20/75 mg/m(2); acute renal failure and febrile neutropenia) and the MTD (febrile neutropenia and hypersensitivity despite pre-medication) were as expected for taxane/platinum combinations. For the 18 patients treated at the MTD, the most frequent possibly related non-hematologic treatment-emergent adverse events (Grade ≥ 3) were nausea (16.7%), fatigue, acute renal failure and decreased appetite (each 11.1%). Neutropenia was the most frequent treatment-emergent Grade ≥ 3 hematologic laboratory abnormality at the MTD (77.8%). The best overall response at the MTD was stable disease, observed in 66.7% of patients. PK results of the combination did not appear to differ from single-agent administration for each agent. CONCLUSION: Combination treatment with cabazitaxel/cisplatin had a manageable safety profile; no PK interactions were evident. The recommended Phase II dose for this combination is cabazitaxel/cisplatin 15/75 mg/m(2) administered every 3 weeks. Antitumor activity findings suggest that further evaluation of this combination in disease-specific trials is warranted.

AKT/mTOR signaling modulates resistance to endocrine therapy and CDK4/6 inhibition in metastatic breast cancers.

Endocrine therapy (ET) in combination with CDK4/6 inhibition is routinely used as first-line treatment for HR+/HER2- metastatic breast cancer (MBC) patients. However, 30-40% of patients quickly develop disease progression. In this open-label multicenter clinical trial, we utilized a hypothesis-driven protein/phosphoprotein-based approach to identify predictive markers of response to ET plus CDK4/6 inhibition in pre-treatment tissue biopsies. Pathway-centered signaling profiles were generated from microdissected tumor epithelia and surrounding stroma/immune cells using the reverse phase protein microarray. Phosphorylation levels of the CDK4/6 downstream substrates Rb (S780) and FoxM1 (T600) were higher in patients with progressive disease (PD) compared to responders (p = 0.02). Systemic PI3K/AKT/mTOR activation in tumor epithelia and stroma/immune cells was detected in patients with PD. This activation was not explained by underpinning genomic alterations alone. As the number of FDA-approved targeted compounds increases, functional protein-based signaling analyses may become a critical component of response prediction and treatment selection for MBC patients.

Autophagy inhibition enhances vorinostat-induced apoptosis via ubiquitinated protein accumulation.

Autophagy is an evolutionarily conserved cell survival pathway that enables cells to recoup ATP and other critical biosynthetic molecules during nutrient deprivation or exposure to hypoxia, which are hallmarks of the tumour microenvironment. Autophagy has been implicated as a potential mechanism of resistance to anticancer agents as it can promote cell survival in the face of stress induced by chemotherapeutic agents by breaking down cellular components to generate alternative sources of energy. Disruption of autophagy with chloroquine (CQ) induces the accumulation of ubiquitin-conjugated proteins in a manner similar to the proteasome inhibitor bortezomib (BZ). However, CQ-induced protein accumulation occurs at a slower rate and is localized to lysosomes in contrast to BZ, which stimulates rapid buildup of ubiquitinated proteins and aggresome formation in the cytosol. The histone deacetylase (HDAC) inhibitor vorinostat (VOR) blocked BZ-induced aggresome formation, but promoted CQ-mediated ubiquitinated protein accumulation. Disruption of autophagy with CQ strongly enhanced VOR-mediated apoptosis in colon cancer cells. Accordingly, knockdown of the essential autophagy gene Atg7 also sensitized cells to VOR-induced apoptosis. Knockdown of HDAC6 greatly enhanced BZ-induced apoptosis, but only marginally sensitized cells to CQ. Subsequent studies determined that the CQ/VOR combination promoted a large increase in superoxide generation that was required for ubiquitinated protein accumulation and cell death. Finally, treatment with the CQ/VOR combination significantly reduced tumour burden and induced apoptosis in a colon cancer xenograft model. Collectively, our results establish that inhibition of autophagy with CQ induces ubiquitinated protein accumulation and VOR potentiates CQ-mediated aggregate formation, superoxide generation and apoptosis.

A Phase I Study of ASTX660, an Antagonist of Inhibitors of Apoptosis Proteins, in Adults with Advanced Cancers or Lymphoma.

PURPOSE: This first-in-human, phase I study evaluated ASTX660, an oral, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins in patients with advanced solid tumors or lymphoma. PATIENTS AND METHODS: ASTX660 was administered orally once daily on a 7-day-on/7-day-off schedule in a 28-day cycle. Dose escalation followed a standard 3+3 design to determine the MTD and recommended phase II dose (RP2D). Dose expansion was conducted at the RP2D. RESULTS: Forty-five patients received ASTX660 (range 15-270 mg/day). Dose-limiting toxicity of grade 3 increased lipase with or without increased amylase occurred in 3 patients at 270 mg/day and 1 patient at 210 mg/day. The MTD was determined to be 210 mg/day and the RP2D 180 mg/day. Common treatment-related adverse events included fatigue (33%), vomiting (31%), and nausea (27%). Grade ≥3 treatment-related adverse events occurred in 7 patients, most commonly anemia (13%), increased lipase (11%), and lymphopenia (9%). ASTX660 was rapidly absorbed, with maximum concentration achieved at approximately 0.5-1.0 hour. An approximately 2-fold accumulation in AUC exposures was observed on day 7 versus 1. ASTX660 suppressed cellular inhibitor of apoptosis protein-1 in peripheral blood mononuclear cells, which was maintained into the second cycle beyond the off-therapy week at the 180-mg/day RP2D and above. Clinical activity was seen in a patient with cutaneous T-cell lymphoma. CONCLUSIONS: ASTX660 demonstrated a manageable safety profile and exhibited evidence of pharmacodynamic and preliminary clinical activity at the 180-mg/day RP2D. The phase II part of the study is ongoing.

Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics.

Survivin, a member of the family of inhibitor of apoptosis proteins, functions as a key regulator of mitosis and programmed cell death. Initially, survivin was described as an inhibitor of caspase-9. However, over the last years, research studies have shown that the role of survivin in cancer pathogenesis is not limited to apoptosis inhibition but also involves the regulation of the mitotic spindle checkpoint and the promotion of angiogenesis and chemoresistance. Survivin gene expression is transcriptionally repressed by wild-type p53 and can be deregulated in cancer by several mechanisms, including gene amplification, hypomethylation, increased promoter activity, and loss of p53 function. This article reviews the multiple functions of survivin in the regulation of apoptosis, the promotion of tumorigenesis, and the development of survivin inhibitors as a novel anticancer therapeutic strategy.

Targeting the mTOR pathway using deforolimus in cancer therapy.

The mammalian target of rapamycin (mTOR) is an intracellular protein with a key role in cellular protein synthesis and energy balance that influences many aspects of cell growth and proliferation, including differentiation, cell-cycle progression, angiogenesis, protein degradation and apoptosis. mTOR can be activated by numerous oncogenic signals, such as growth factor activation through the EGF, IGF and VEGF receptors, mutation and silencing of the PTEN tumor suppressor gene, activating mutations in the PI3K catalytic subunit, Akt amplification and the Ras-Raf-MEK pathway. Once activated, the cellular functions of mTOR are achieved through its downstream targets, 4E-BP1 and p70S6K1. The mTOR pathway can be further regulated through a negative feedback loop, which may lead to resistance to specific inhibitors of mTOR. This review will outline the mTOR signaling pathway, which is often activated in cancers and account for tumor proliferation and growth, highlight the rationale in targeting mTOR with a focus on the preclinical and clinical development of one of these inhibitors, deforolimus (AP23573, MK-8669), and discuss potential benefit and barriers to these agents being introduced in the clinic.

PARP Inhibition in Cancer: An Update on Clinical Development.

PARP (poly(ADP-ribose) polymerase) inhibitors represent a novel class of anti-cancer therapy; they take advantage of synthetic lethality and induce cell death by exploiting a defect in DNA repair. This class of medication was initially evaluated in patients with BRCA-associated tumors, but efficacy was also demonstrated in other populations. Since 2014, four PARP inhibitors have been approved in various indications: olaparib, niraparib, and rucaparib in high-grade serous ovarian cancer, and olaparib and talazoparib in metastatic breast cancer. The exact indications and study populations vary slightly between the different approvals in both disease states but there is significant overlap. PARP inhibitors continue to be investigated in ongoing clinical trials. In line with other targeted therapies, benefit appears to be strongest in a distinct population of patients with BRCA mutations or other defects in homologous recombination repair. Combination therapies, which include anti-angiogenesis agents and immunotherapy, show promise as a strategy to broaden efficacy for unselected patients. Initial studies of PARP inhibitors in combination with chemotherapy were limited by toxicity, but further studies are underway. To date, head-to-head trials comparing various PARP inhibitors have not been conducted, so questions remain in terms of choosing a PARP inhibitor to administer when indications overlap, as well as how to sequence these medications. Here we review both completed and ongoing clinical trials involving PARP inhibitors and mechanisms of resistance to this class of drugs.

Phase I and pharmacokinetic study of AI-850, a novel microparticle hydrophobic drug delivery system for paclitaxel.

PURPOSE: AI-850, paclitaxel in a novel polyoxyethylated castor oil-free hydrophobic microparticle delivery system, is being developed based on its favorable preclinical safety and antitumor activity profiles. The objectives of the study were to assess the feasibility and safety of administering AI-850 as a <30-min i.v. infusion without premedication every 3 weeks, determine the maximum tolerated dose and the phase II recommended dose of AI-850, study the pharmacokinetics of paclitaxel in this new formulation, and seek evidence of anticancer activity. EXPERIMENTAL DESIGN: This was an open-label phase I dose escalation study of AI-850 in patients with advanced solid malignancies. AI-850 doses were escalated according to a modified Fibonacci scheme. Clinical and laboratory toxicity was monitored, and paclitaxel plasma concentrations were measured by liquid chromatography-tandem mass spectrometry. RESULTS: Twenty-two patients received 56 courses of AI-850 at five dose cohorts ranging from 36 to 250 mg/m(2). Grade 4 neutropenia, either exceeding 5 days or complicated by fever, was dose limiting in two of six patients at 250 mg/m(2) AI-850. Three patients experienced grade 2 to 4 infusion-related adverse reactions. Toxicities, including fatigue, alopecia, nausea and vomiting, neuropathy, anorexia, and myalgia, were mild to moderate, reversible, and not dose related. Pharmacokinetics of free and total paclitaxel showed biexponential plasma decay and dose proportionality for maximum plasma paclitaxel concentration and area under the concentration versus time curve. Antitumor activity was documented in two patients with endometrial and tongue carcinomas. CONCLUSIONS: The administration of AI-850 as a brief infusion once every 3 weeks was feasible at doses up to 205 mg/m(2). The potential of AI-850 as an alternative to other approved paclitaxel formulations requires further clinical evaluation.

A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naïve patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that pelareorep complements single agent gemcitabine in PDAC.

A phase II, pharmacokinetic, and biologic study of semaxanib and thalidomide in patients with metastatic melanoma.

PURPOSE: This phase II study evaluated the combination of semaxanib, a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor-2, and thalidomide in patients with metastatic melanoma to assess the efficacy, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the combination. PATIENTS AND METHODS: Patients with metastatic melanoma, who had failed at least one prior biologic and/or chemotherapeutic regimen, were treated with escalating doses of thalidomide combined with a fixed dose of semaxanib. RESULTS: Twelve patients were enrolled and received 44 courses of semaxanib at the fixed dose of 145 mg/m2 intravenously twice-weekly in combination with thalidomide, commencing at 200 mg daily with intrapatient dose escalation as tolerated. Treatment with semaxanib was initiated 1 day before thalidomide in the first course, permitting the assessment of the PKs of semaxanib alone (course 1) and in combination with thalidomide (course 2). The principal toxicities included deep venous thrombosis, headache, and lower extremity edema. Of ten patients evaluable for response, one complete response lasting 20 months and one partial response lasting 12 months were observed. Additionally, four patients had stable disease lasting from 2 to 10 months. The PKs of semaxanib were characterized by drug exposure parameters comparable to those observed in single-agent phase II studies, indicating the absence of major drug-drug interactions. Maximum semaximib plasma concentration values were 1.2-3.8 microg/ml in course 1 and 1.1-3.9 microg/ml in course 2. The mean terminal half-life was 1.3 ( +/- 0.31) h. Biological studies revealed increasing serum VEGF concentrations following treatment in patients remaining on study for more than 4 months. CONCLUSION: The combination of semaxanib and thalidomide was feasible and demonstrated anti-tumor activity in patients with metastatic melanoma who had failed prior therapy. Further evaluations of therapeutic strategies that target multiple angiogenesis pathways may be warranted in patients with advanced melanoma and other malignancies.

Phase I, pharmacokinetic, and biological study of erlotinib in combination with paclitaxel and carboplatin in patients with advanced solid tumors.

PURPOSE: To assess the feasibility of administering erlotinib, an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, in combination with paclitaxel and carboplatin, and to identify pharmacokinetic interactions, evaluate downstream effects of EGFR inhibition on surrogate tissues, and seek preliminary evidence for clinical activity. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated continuously with erlotinib at doses of 100, 125, and 150 mg/d orally along with fixed i.v. doses of paclitaxel 225 mg/m(2) and carboplatin AUC 6 mg x min/mL, both on day 1 every 3 weeks. RESULTS: Twenty evaluable patients were treated with 136 courses of erlotinib, paclitaxel, and carboplatin. Myelosuppression, skin rash, and diarrhea were the principal toxicities. Dose limiting diarrhea occurred in 1 of 6 patients at the 100 mg erlotinib dose level, whereas 0 of 9 evaluable patients at the 125 mg erlotinib dose level experienced dose limiting toxicity and 3 of 5 evaluable patients at 150 mg erlotinib experienced dose limiting skin rash and neutropenic sepsis. There was no evidence of pharmacokinetic interactions between paclitaxel and erlotinib; however, total carboplatin exposure trended higher in the presence of erlotinib. No consistent downstream effects on EGFR inhibition were found in skin. Durable objective responses were observed in non-small-cell lung and head and neck cancers. CONCLUSIONS: A dose level of erlotinib 125 mg combined with paclitaxel 225 mg/m(2) and carboplatin AUC 6 mg.min/mL is recommended for disease-directed studies. This phase I trial was followed by a randomized phase III study in non-small-cell lung cancer using a similar regimen.

Statins and pancreatic cancer.

Pancreatic cancer remains among the most lethal cancers, despite ongoing advances in treatment for all stages of the disease. Disease prevention represents another opportunity to improve patient outcome, with metabolic syndrome and its components, such as diabetes, obesity and dyslipidemia, having been recognized as modifiable risk factors for pancreatic cancer. In addition, statins have been shown to potentially reduce pancreatic cancer risk and to improve survival in patients with a combination of metabolic syndrome and pancreatic cancer. Furthermore, preclinical studies have demonstrated that statins exhibit antitumor effects in pancreatic cancer cell lines in vitro and animal models in vivo, in addition to delaying the progression of pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma (PDAC) and inhibiting PDAC formation in conditional K-Ras mutant mice. The mechanisms by which statins produce anticancer effects remain poorly understood, although appear to involve inhibition of the mevalonate/cholesterol synthesis pathway, thus blocking the synthesis of intermediates important for prenylation and activation of the Ras/mitogen-activated protein kinase 1 signaling pathway. Furthermore, statins have been identified to modulate the phosphoinositide 3-kinase/Akt serine/threonine kinase 1 and inflammation signaling pathways, and to alter the expression of genes involved in lipid metabolism, which are important for PDAC growth and proliferation. In addition, statins have been demonstrated to exhibit further antitumor mechanisms in a number of other cancer types, which are beyond the scope of the present review. In the present review, current evidence highlighting the potential of statins as chemopreventive agents in pancreatic cancer is presented, and the antitumor mechanisms of statins elucidated thus far in this disease are discussed.

Oncolytic reovirus inhibits angiogenesis through induction of CXCL10/IP-10 and abrogation of HIF activity in soft tissue sarcomas.

The tumor-selective viral replication capacity and pro-apoptotic effects of oncolytic reovirus have been reported to be dependent on the presence of an activated RAS pathway in several solid tumor types. However, the mechanisms of selective anticancer efficacy of the reovirus-based formulation for cancer therapy (Reolysin, pelareorep) have not been rigorously studied in soft tissue sarcomas (STS). Here we report that Reolysin triggered a striking induction of the anti-angiogenic chemokine interferon-γ-inducible protein 10 (IP-10)/CXCL10 (CXC chemokine ligand 10) in both wild type and RAS mutant STS cells. Further analysis determined that Reolysin treatment possessed significant anti-angiogenic activity irrespective of RAS status. In addition to CXCL10 induction, Reolysin dramatically downregulated the expression of hypoxia inducible factor (HIF)-1α, HIF-2α and inhibited vascular endothelial growth factor (VEGF) secretion. CXCL10 antagonism significantly diminished the anti-angiogenic effects of Reolysin indicating that it is a key driver of this phenomenon. Xenograft studies demonstrated that Reolysin significantly improved the anticancer activity of the anti-angiogenic agents sunitinib, temsirolimus, and bevacizumab in a manner that was associated with increased CXCL10 levels. This effect was most pronounced following treatment with Reolysin in combination with temsirolimus. Further analysis in additional sarcoma xenograft models confirmed the significant increase in CXCL10 and increased anticancer activity of this combination. Our collective results demonstrate that Reolysin possesses CXCL10-driven anti-angiogenic activity in sarcoma models, which can be harnessed to enhance the anticancer activity of temsirolimus and other agents that target the tumor vasculature.

Clinical development of reovirus for cancer therapy: An oncolytic virus with immune-mediated antitumor activity.

Reovirus is a double-stranded RNA virus with demonstrated oncolysis or preferential replication in cancer cells. The oncolytic properties of reovirus appear to be dependent, in part, on activated Ras signaling. In addition, Ras-transformation promotes reovirus oncolysis by affecting several steps of the viral life cycle. Reovirus-mediated immune responses can present barriers to tumor targeting, serve protective functions against reovirus systemic toxicity, and contribute to therapeutic efficacy through antitumor immune-mediated effects via innate and adaptive responses. Preclinical studies have demonstrated the broad anticancer activity of wild-type, unmodified type 3 Dearing strain reovirus (Reolysin(®)) across a spectrum of malignancies. The development of reovirus as an anticancer agent and available clinical data reported from 22 clinical trials will be reviewed.

Phase 1 Study of CEP-37250/KHK2804, a Tumor-specific Anti-glycoconjugate Monoclonal Antibody, in Patients with Advanced Solid Tumors.

BACKGROUND: CEP-37250/KHK2804 is a recombinant, humanized, non-fucosylated, monoclonal antibody directed to sialic acid-containing glycoconjugates frequently found on certain tumor cell types. OBJECTIVE: The objective was to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, potential immunogenicity, and preliminary clinical efficacy of CEP-37250/KHK2804 monotherapy in patients with advanced cancer in a first-in-human, phase 1 study. MATERIALS AND METHODS: In phase 1a, patients (n = 31) with solid tumors received increasing doses of CEP-37250/KHK2804 (0.03-1.0 mg/kg) intravenously once weekly using a standard 3 + 3 dose-escalation design. In phase 1b, two dose-expansion cohorts of patients with colorectal (n = 15) and pancreatic (n = 16) cancer, respectively, received the maximum tolerated dose (MTD). RESULTS: The MTD of CEP-37250/KHK2804 was 0.3 mg/kg weekly. Dose-limiting toxicities were infusion-related reactions and increased serum transaminases. In the overall population (N = 62), the most frequent treatment-related adverse event (AE) was an infusion-related reaction (45.2 %). Positive post-baseline CEP-37250/KHK2804 neutralizing antibodies were reported in 14 patients (22.6 %), almost exclusively in patients who developed infusion-related reactions. The most frequent treatment-related AE grade ≥3 was increased AST or ALT in six patients (9.7 %). Three patients experienced treatment-related serious cardiac events (grade 4 ECG abnormality, grade 4 atrial fibrillation, and grade 3 acute myocardial infarction, respectively). Pharmacokinetic exposure to CEP-37250/KHK2804 increased proportionally to dose, with accumulation up to two fold with repeated administration. Mean elimination half-life was 34.1 to 70.3 hours over the dose range from 0.03 to 1.0 mg/kg. No patient had a complete or partial best response. Thirteen of 40 (32.5 %) evaluable patients had unconfirmed stable disease, four of which were confirmed (10.0 %). CONCLUSIONS: The study was stopped early due to the lack of efficacy. Additionally, safety concerns (i.e., cardiac issues, hepatic toxicity, and infusion-related reactions) made the benefit-risk assessment unfavorable for continued development of CEP-37250/KHK2804, which was halted indefinitely. [Study registered at ClinicalTrials.gov #NCT01447732].