A Multicenter Phase II Study of Gemcitabine, Capecitabine, and Bevacizumab for Locally Advanced or Metastatic Biliary Tract Cancer.

OBJECTIVES: Vascular endothelial growth factor overexpression, seen in 42% to 76% of biliary tract cancers (BTCs), correlates with poor survival. We explored the safety/efficacy and potential biomarkers for bevacizumab in combination with gemcitabine-capecitabine in advanced BTCs. PATIENTS AND METHODS: Inoperable stage III/IV BTC patients in our prospective study were given 1000 mg/m of gemcitabine (on days 1, 8), 650 mg/m of capecitabine (on days 1 to 14), and 15 mg/kg of bevacizumab (on day 1) in 21-day cycles. Circulating tumor cells and quality of life were assessed at baseline and before cycle 2 and 3. RESULTS: In total, 50 patients with gallbladder cancer (22%), intrahepatic (58%), and extrahepatic (20%) cholangiocarcinoma, received a median of 8 treatment cycles for median treatment duration of 5.8 months. Common grade 3/4 toxicities were neutropenia (36%), thrombocytopenia (16%), fatigue (20%), infections (14%), and hand-foot syndrome (10%). There were 12 partial response (24%), 24 stable disease (48%) with clinical benefit rate of 72%. Median progression-free survival was 8.1 months (95% confidence interval, 5.3-9.9). Median overall survival was 10.2 months (95% confidence interval, 7.5-13.7). Circulating tumor cells were identified at baseline in 21/46 patients (46%), who had lower median overall survival compared with those without (9.4 vs. 13.7 mo; P=0.29). Patients with quality of life scores greater than the group median by the end of first cycle of treatment had improved survival compared with those who did not (13.3 vs. 9.4 mo; P=0.39). CONCLUSIONS: Addition of bevacizumab to gemcitabine/capecitabine did not improve outcome in an unselected group of patients with advanced BTC compared with historical controls. The selective benefit of vascular endothelial growth factor inhibition in BTC remains to be explored.

A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response.

Long conserved mechanisms maintain homeostasis in living creatures in response to a variety of stresses. However, continuous exposure to stress can result in unabated production of stress hormones, especially catecholamines, which can have detrimental health effects. While the long-term effects of chronic stress have well-known physiological consequences, recent discoveries have revealed that stress may affect therapeutic efficacy in cancer. Growing epidemiological evidence reveals strong correlations between progression-free and long-term survival and ß-blocker usage in cancer patients. In this review, we summarize the current understanding of how the catecholamines, epinephrine and norepinephrine, affect cancer cell survival and tumor progression. We also highlight new data exploring the potential contributions of stress to immunosuppression in the tumor microenvironment and the implications of these findings for the efficacy of immunotherapies.

Physiologically based pharmacokinetic models for everolimus and sorafenib in mice.

PURPOSE: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved as an immunosuppressant and for second-line therapy of hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Sorafenib is a multikinase inhibitor used as first-line therapy in HCC and RCC. This study assessed the pharmacokinetics (PK) of everolimus and sorafenib alone and in combination in plasma and tissues, developed physiologically based pharmacokinetic (PBPK) models in mice, and assessed the possibility of PK drug interactions. METHODS: Single and multiple oral doses of everolimus and sorafenib were administered alone and in combination in immunocompetent male mice and to severe combined immune-deficient (SCID) mice bearing low-passage, patient-derived pancreatic adenocarcinoma in seven different studies. Plasma and tissue samples including tumor were collected over a 24-h period and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Distribution of everolimus and sorafenib to the brain, muscle, adipose, lungs, kidneys, pancreas, spleen, liver, GI, and tumor was modeled as perfusion rate-limited, and all data from the diverse studies were fitted simultaneously using a population approach. RESULTS: PBPK models were developed for everolimus and sorafenib. PBPK analysis showed that the two drugs in combination had the same PK as each drug given alone. A twofold increase in sorafenib dose increased tumor exposure tenfold, thus suggesting involvement of transporters in tumor deposition of sorafenib. CONCLUSIONS: The developed PBPK models suggested the absence of PK interaction between the two drugs in mice. These studies provide the basis for pharmacodynamic evaluation of these drugs in patient-derived primary pancreatic adenocarcinomas explants.

Synergistic interactions between sorafenib and everolimus in pancreatic cancer xenografts in mice.

PURPOSE: Molecular targeting of cellular signaling pathways is a promising approach in cancer therapy, but often fails to achieve sustained benefit because of the activation of collateral cancer cell survival and proliferation pathways. We tested the hypothesis that a combination of targeted agents that inhibit compensatory pathways would be more effective than single agents in controlling pancreatic cancer cell growth. We investigated whether everolimus, an mTOR inhibitor, and sorafenib, a multi-kinase inhibitor, would together inhibit growth of low-passage, patient-derived pancreatic cancer xenografts in mice more efficaciously than either agent alone. METHODS: Tumor volume progression was measured following treatment with both drugs as single agents, in combination, and at multiple doses. Pharmacokinetics in tumors and other tissues was also assessed. Pharmacodynamic interactions were evaluated quantitatively. RESULTS: A 5-week regimen of daily oral doses of 10 mg/kg sorafenib and 0.5 mg/kg everolimus, alone and in combination, did not achieve significant tumor growth inhibition. Higher doses (20 mg/kg of sorafenib and 1 mg/kg of everolimus) inhibited tumor growth significantly when given alone and caused complete inhibition of growth when given in combination. Tumor volume progression was described by a linear growth model, and drug effects were described by Hill-type inhibition. Using population modeling approaches, dual-interaction parameter estimates indicated a highly synergistic pharmacodynamic interaction between the two drugs. CONCLUSIONS: The results indicate that combinations of mTOR and multi-kinase inhibitors may offer greater efficacy in pancreatic cancer than either drug alone. Drug effects upon tumor stromal elements may contribute to the enhanced anti-tumor efficacy.

Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766 in patients with advanced cancer.

PURPOSE: To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors. EXPERIMENTAL DESIGN: BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signal-regulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes. RESULTS: Sixty-nine patients were enrolled, including 20 patients at the MTD. The MTD was 100 mg given once-daily or in two divided doses. BAY 86-9766 was well-tolerated. The most common treatment-related toxicities were acneiform rash and gastrointestinal toxicity. BAY 86-9766 was well-absorbed after oral administration (plasma half-life ~12 hours), and displayed dose proportional pharmacokinetics throughout the tested dose range. Continuous daily dosing resulted in moderate accumulation at most dose levels. BAY 86-9766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetate-stimulated peripheral blood leukocytes. Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy. CONCLUSION: This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types.

Interactions of everolimus and sorafenib in pancreatic cancer cells.

Everolimus targets the mammalian target of rapamycin, a kinase that promotes cell growth and proliferation in pancreatic cancer. Sorafenib inhibits the Raf-mitogen-activated protein kinase, vascular endothelial growth factor, and platelet-derived growth factor pathways, thus inhibiting cell growth and angiogenesis. Combinations of these two agents are under evaluation for therapy of several cancers. This study examined the effects of everolimus and sorafenib on proliferation of the pancreatic cancer cell lines MiaPaCa-2 and Panc-1. Cell growth inhibition was evaluated in vitro for a range of concentrations of the drugs alone and in combination. Maximum inhibition capacity (I (max)) and potency (IC(50)) were determined. The data were analyzed to characterize drug interactions using two mathematical analysis techniques. The Ariens noncompetitive interaction model and Earp model were modified to accommodate alterations in the inhibition parameters of one drug in the presence of another. Sorafenib alone inhibited growth of both cell lines completely (I (max) = 1), with an IC(50) of 5-8 µM. Maximal inhibition by everolimus alone was only 40% (I (max) = 0.4) in both cell lines, with an IC(50) of 5 nM. Slight antagonistic interaction occurred between the drugs; both analytic methods estimated the interaction term Ψ as greater than 1 for both cell lines. The in vitro data for two pancreatic cancer cell lines suggest that a combination of these two drugs would be no more efficacious than the individual drugs alone, consistent with the drug interaction analysis that indicated slight antagonism for growth inhibition.

Interactions of everolimus and sorafenib in whole blood lymphocyte proliferation.

PURPOSE: Everolimus is an immunosuppressant that blocks growth factor-mediated proliferation of hematopoietic cells by targeting the mammalian target of rapamycin (mTOR). Sorafenib is a multikinase inhibitor that inhibits cell proliferation by arresting cells in the G0-G1 phase of the cell cycle. These agents are under investigation as combination therapy for various cancers. Because the two drugs individually inhibit lymphocyte proliferation, this study examined the effects of everolimus and sorafenib on lymphocyte proliferation in order to anticipate possible immunosuppression. METHODS: Inhibition of lymphocyte proliferation was evaluated ex vivo over a range of concentrations of these drugs, alone and in combination. Data analysis, using a population approach to characterize interactions, employed the Ariens noncompetitive interaction model, which was modified to accommodate interactions of the two drugs. RESULTS: Everolimus alone caused partial inhibition of lymphocyte proliferation, with a mean IC(50) of 4.5 nM for females and 10.5 nM in males. Sorafenib alone caused complete inhibition, with a mean IC(50) of 11.4 µM and no difference between genders. CONCLUSION: The population estimate for the interaction term was greater than 1, suggesting that the two drugs exert slight antagonism in terms of inhibition of lymphocyte proliferation.

Dual targeting of mTORC1/C2 complexes enhances histone deacetylase inhibitor-mediated anti-tumor efficacy in primary HCC cancer in vitro and in vivo.

BACKGROUND & AIMS: The mammalian target of rapamycin (mTOR) plays a pivotal role in hepatocellular carcinoma (HCC). Previous studies indicated that inhibition of mTORC1 enhanced histone deacetylase inhibitors (HDACis)-mediated anti-tumor activity, accompanied with feedback activation of AKT. Therefore, dual targeting of mTORC1/C2 should be more efficient in suppressing AKT activity and in enhancing the anti-tumor activity of HDACi in HCC. METHODS: The interactions between mTOR kinase inhibitors (mTORKis) (i.e., Pp242, AZD8055, OSI027) and HDACis (i.e., SAHA, LBH589) were examined in vitro using HCC cell lines and in vivo using patient-derived primary HCC xenografts on SCID mice. RESULTS: mTORKis significantly enhanced HDACi-induced apoptosis in HCC cells. The inhibition of both mTORC1/2 not only efficiently blocked mTORC1 signaling, but also abrogated AKT-feedback activation caused by selective mTORC1 inhibition. The co-treatment of mTORKi and HDACi further inhibited AKT signaling and upregulated Bim. Dysfunction of mTORC2 by shRNA significantly lowered the threshold of HDACi-induced cytotoxicity by abrogating AKT activation. Knockdown of AKT1 sensitized Pp242/HDACi-induced apoptosis and ectopic expression of constitutively active AKT1 abrogated the combination-induced cytotoxicity, indicating AKT plays a vital role in the combination-induced effects. Knockdown of Bim prevented Pp242/HDACis-induced cytotoxicity in HCC. Lastly, in vivo studies indicated that the combination of AZD8055 and SAHA almost completely inhibited tumor-growth, without obvious adverse effects, by abrogating AKT and upregulating Bim; while either agent alone shows only 30% inhibition in primary HCC xenografts. CONCLUSIONS: Our findings suggest that a combining-regimen of mTORKi and HDACi may be an effective therapeutic strategy for HCC.

Emerging therapies in pancreas cancer.

Pancreas cancer has a grave prognosis and treatment options remain limited despite advancement in anti-cancer chemotherapeutics. This review provides an overview of the emerging therapies for pancreas cancer, focusing on novel signal transduction inhibitors (insulin-like growth factor receptor, hedgehog/Smo, PI3k/Akt/mTOR) and cytotoxics (nab-paclitaxel) that are currently in clinical development. Despite the impact molecularly targeted agents have on other tumor types, their application without cytotoxics in pancreas cancer remains limited. In addition, recent report of the superiority of an intensive cytotoxic regimen using fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) over gemcitabine reminded us of the importance of cytotoxics in this disease. As such, the future of pancreas cancer therapy may be combination regimens consisting of cytotoxics and molecularly targeted agents.

Analysis of clinical and dosimetric factors associated with change in renal function in patients with gastrointestinal malignancies after chemoradiation to the abdomen.

PURPOSE: To analyze clinical and dosimetric factors associated with change in renal function in patients with gastrointestinal malignancies after chemoradiation to the abdomen. METHODS AND MATERIALS: A retrospective review of 164 patients with gastrointestinal malignancies treated between 2002 and 2007 was conducted to evaluate change in renal function after concurrent chemotherapy and three-dimensional conformal abdominal radiotherapy (RT). Laboratory and biochemical endpoints were determined before RT and after RT at 6-month intervals. Factors assessed included smoking, diabetes, hypertension, blood urea nitrogen, creatinine, creatinine clearance (CrCl), chemotherapy, and dose-volume parameters. Renal toxicity was assessed by decrease in CrCl and scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring schema. RESULTS: Of 164 patients, 63 had clinical and dosimetric data available. Median follow-up was 17.5 months. Creatinine clearance declined from 98.46 mL/min before RT to 74.20 mL/min one year after chemoradiation (p < 0.0001). Mean decrease in CrCl was 21.37%. Pre-RT CrCl, percentage of bilateral renal volume receiving at least 10 Gy (V(10)), and mean kidney dose were significantly associated with development of Grade > or =2 renal complications at 1 year after chemoradiation (p = 0.0025, 0.0170, and 0.0095, respectively). CONCLUSIONS: We observed correlation between pre-RT CrCl, V(10), and mean kidney dose and decline in CrCl 1 year after chemoradiation. These observations can assist in treatment planning and renal dose constraints in patients receiving chemotherapy and abdominal RT and may help identify patients at increased risk for renal complications.

Novel agents on the horizon for cancer therapy.

Although cancer remains a devastating diagnosis, several decades of preclinical progress in cancer biology and biotechnology have recently led to successful development of several biological agents that substantially improve survival and quality of life for some patients. There is now a rich pipeline of novel anticancer agents in early phase clinical trials. The specific tumor and stromal aberrancies targeted can be conceptualized as membrane-bound receptor kinases (HGF/c-Met, human epidermal growth factor receptor and insulin growth factor receptor pathways), intracellular signaling kinases (Src, PI3k/Akt/mTOR, and mitogen-activated protein kinase pathways), epigenetic abnormalities (DNA methyltransferase and histyone deacetylase), protein dynamics (heat shock protein 90, ubiquitin-proteasome system), and tumor vasculature and microenvironment (angiogenesis, HIF, endothelium, integrins). Several technologies are available to target these abnormalities. Of these, monoclonal antibodies and small-molecule inhibitors have been the more successful, and often complementary, approaches so far in clinical settings. The success of this target-based cancer drug development approach is discussed with examples of recently approved agents, such as bevacizumab, erlotinib, trastuzumab, sorafenib, and bortezomib. This review also highlights the pipeline of rationally designed drugs in clinical development that have the potential to impact clinical care in the near future.

Temsirolimus.

Temsirolimus (CCI-779), a small molecule inhibitor of mTOR protein, is a water-soluble synthetic rapamycin ester that has been developed in both oral and intravenous (i.v.) formulations. PI3k/Akt/mTOR pathway activation is implicated in the pathogenesis of many cancers. Inhibition of mTOR protein abrogates pathway-mediated cellular transcription and translation, leading to cell cycle arrest, antiangiogenesis and apoptosis. The drug has significant in vitro antitumor effect against a number of cancer cell lines and has demonstrated in vivo cytostatic activity in xenograft models. Flat dosing of 25 mg, 75 mg and 250 mg i.v. weekly were selected for tumor-specific phase I trials. Biological activity was observed at all these doses. However, the frequency and intensity of the toxicities increased at higher doses and more high-dose patients had to reduce the dose or discontinue the drug. Notable temsirolimus-related toxicities include rash, mucostomatitis, diarrhea, hyperlipidemia, hyperglycemia and thrombocytopenia. Temsirolimus is farther along in clinical development than any other mTOR inhibitor in its class and has demonstrated significant activity in patients with poor-risk clear-cell renal cell carcinoma. Patients receiving temsirolimus alone achieved longer survival than those receiving interferon alone or temsirolimus plus interferon in a randomized phase III trial. Predictive biomarkers for clinical efficacy are undetermined and remain under investigation.

Exploiting novel molecular targets in gastrointestinal cancers.

Novel molecular targets are being discovered as we learn more about the aberrant processes underlying various cancers. Efforts to translate this knowledge are starting to impact on the care of patients with gastrointestinal cancers. The epidermal growth factor receptor (EGFR) pathway and angiogenesis have been targeted successfully in colorectal cancer with cetuximab, panitunumab and bevacizumab. Similarly, EGFR-targeting with erlotinib yielded significant survival benefit in pancreatic cancer when combined with gemcitabine. The multi-targeting approach with sorafenib has made it the first agent to achieve significant survival benefit in hepatocellular carcinoma. Efforts to exploit the dysregulated Akt/mTOR pathway in GI cancer therapy are ongoing. These molecular targets can be disrupted by various approaches, including the use of monoclonal antibody to intercept extracellular ligands and disrupt receptor-ligand binding, and small molecule inhibitors that interrupt the activation of intracellular kinases.

Strategies for suppressing angiogenesis in gynecological cancers.

Angiogenesis is vital for numerous physiological and pathological processes, including proliferation, invasion and metastasis in malignancies. Various strategies to suppress angiogenesis are under evaluation in gynecological malignancies, and ovarian cancer--the deadliest of them--has been the focus. Interruption of interaction between vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) with a monoclonal antibody, bevacizumab, has so far been the most promising antiangiogenic strategy in ovarian cancer clinically but is overshadowed by higher than expected frequency of severe toxicities. Interception of VEGF with receptor decoys, such as VEGF-Trap, and inhibiting receptor tyrosine kinases for VEGF and related growth factors with small molecule inhibitors have shown encouraging results in early phase trials of ovarian cancer; validation is ongoing in larger studies. Another approach is targeting pre-mRNA for VEGF receptors with ribozyme (angiozyme). The knowledge gained from developing these different classes of antiangiogenic agents will lay the path to future trials of other types of gynecological cancers.