Direct co-operation between sensitiser molecules BAD and NOXA in mediating apoptosis suggests that therapeutic agents which sensitise to BAD may complement agents which sensitise to NOXA. Dynamic BH3 profiling is a novel methodology that we have applied to the measurement of complementarity between sensitiser BH3 peptide mimetics and therapeutic agents. Using dynamic BH3 profiling, we show that the agent TG02, which downregulates MCL-1, sensitises to the BCL-2-inhibitory BAD-BH3 peptide, whereas the BCL-2 antagonist ABT-199 sensitises to MCL-1 inhibitory NOXA-BH3 peptide in acute myeloid leukaemia (AML) cells. At the concentrations used, the peptides did not trigger mitochondrial outer membrane permeabilisation in their own right, but primed cells to release Cytochrome C in the presence of an appropriate trigger of a complementary pathway. In KG-1a cells TG02 and ABT-199 synergised to induce apoptosis. In heterogeneous AML patient samples we noted a range of sensitivities to the two agents. Although some individual samples markedly favoured one agent or the other, in the group as a whole the combination of TG02 + ABT-199 was significantly more cytotoxic than either agent individually. We conclude that dynamic NOXA and BAD BH3 profiling is a sensitive methodology for investigating molecular pathways of drug action and complementary mechanisms of chemoresponsiveness.

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On April 20, 2016 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that it has presented the results of non-clinical research investigating the combination of Eisai’s in-house developed anticancer agent lenvatinib mesylate (lenvatinib) and anticancer agent everolimus at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 107th Annual Meeting (Press release, Eisai, APR 20, 2016, View Source [SID:1234511115]). The presentations concerned an analysis of the mechanism of action that leads to enhanced inhibition of angiogenesis as well as using murine models to demonstrate an anti-tumor effect on renal cell carcinoma.

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As the results of research presented at the AACR (Free AACR Whitepaper) meeting,1 when the combination of lenvatinib (7.5 mg/kg) and everolimus (15 mg/kg), lenvatinib alone (10 mg/kg) or everolimus alone (30 mg/kg) were administered to model mice in which tumor angiogenesis had been induced from overexpression of either vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF), a substantial inhibitory effect on tumor growth was observed in both types of mice that had been administered the combination therapy compared to the higher doses of lenvatinib alone or everolimus alone. As subsequent in vitro studies, in VEGF and FGF stimulated human umbilical vascular endothelial cells, it was observed that lenvatinib inhibits VEGF and FGF receptors while everolimus suppresses the downstream signaling pathways for these two receptors, confirming that enhanced antiangiogenic activity is due to the mechanisms of action of both agents combined. Furthermore, it is suggested that the combination of lenvatinib and everolimus synergistically enhances inhibitory activity against FGF-induced angiogenesis as well.

In separate research findings,2 in a xenograft model where human renal cell carcinoma cell strains had been implanted subcutaneously into mice, when the combination of lenvatinib (10 mg/kg) and everolimus (30 mg/kg), lenvatinib alone (10 mg/kg) or everolimus alone (30 mg/kg) were administered to these mice, pronounced apoptosis in tumor cells was observed only in the group that received combination therapy. Furthermore, a decrease in microvessel density for lenvatinib alone and a decrease in the proportion of proliferative cells for everolimus alone were seen, and both these effects were observed in the combination therapy group. These results suggest that treatment of lenvatinib in combination with everolimus causes a strong antitumor effect by combining the potent antiangiogenic activity of lenvatinib as well as direct antitumor activity of everolimus.

Eisai remains committed to providing further clinical evidence for lenvatinib aimed at maximizing value of the drug as it seeks to contribute further to addressing the diverse needs of, and increasing the benefits provided to, patients with cancer, their families, and healthcare providers.

1. About lenvatinib mesylate (generic name, "lenvatinib", product name: Lenvima)
Lenvatinib is an orally administered multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2 and VEGFR3) and fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3 and FGFR4) in addition to other proangiogenic and oncogenic pathway-related RTKs (including the platelet-derived growth factor (PDGF) receptor PDGFRα; KIT; and RET) involved in tumor proliferation.
Currently, Eisai has obtained approval for lenvatinib in over 40 countries including the United States, Japan, Europe, Korea and Canada as a treatment for refractory thyroid cancer, and is undergoing regulatory review in countries throughout the world including in Asia, Russia, Australia, Brazil and Mexico. More specifically, Eisai has obtained approval for the agent indicated in the United States for treatment for locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer, in Japan for the treatment of unresectable thyroid cancer, and in Europe for the treatment of adult patients with progressive, locally advanced or metastatic differentiated (papillary, follicular, Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine, respectively. Meanwhile, Eisai is conducting a global Phase III study of lenvatinib in hepatocellular carcinoma, Phase II studies of lenvatinib in several other tumor types such as endometrial carcinoma and biliary tract cancer, as well as a Phase Ib/II study of lenvatinib in combination with an immune checkpoint inhibitor.

2. About Renal Cell Carcinoma
The number of patients with renal cancer was estimated to be approximately 338,000 worldwide, including approximately 58,000 in the United States, 115,000 in Europe and 17,000 in Japan.3 Renal cell carcinoma comprises more than 90% of all malignancies of the kidney,4 and occurs when malignant cells are found in the lining of the tubules of the kidney. The incidence of renal cell carcinoma in people aged in their late 50s is rising, and is more likely to affect men than women. For advanced or metastatic renal cell carcinoma that is difficult to treat with surgery, the standard treatment method is molecular targeted drug therapy, however with low 5-year survival rates, this remains a disease with significant unmet medical need.

On April 20, 2016 Curis, Inc. (NASDAQ:CRIS), a biotechnology company focused on the development and commercialization of innovative and effective drug candidates for the treatment of human cancers, reported that Curis and its collaborator, Aurigene, presented data from the following programs at the Annual Meeting of American Association of Cancer Research (AACR) (Free AACR Whitepaper) in New Orleans, LA (Press release, Curis, APR 20, 2016, View Source [SID:1234511139]).

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Curis poster presentation on CUDC-907, an oral inhibitor of histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K)

Aurigene presentation on CA-170 (previously AUPM-170), a first-in-class oral, small molecule immune checkpoint antagonist targeting programmed death ligand-1 (PD-L1) and V-domain Ig suppressor of T cell activation (VISTA), as well as data from the PD-L1/ T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) antagonist program

Aurigene presentation on CA-4948, the lead compound from the interleukin-1 receptor associated kinase 4 (IRAK4) inhibitor program
"Our data show significant effect of CUDC-907 on MYC levels and the compound’s antitumor activity in multiple preclinical models of MYC-altered malignancies, providing further support to the results of our Phase 1 trial where we observed objective responses in patients with DLBCL, and particularly those with MYC-altered disease," said Ali Fattaey, Ph.D., Curis’ President and CEO. "The presentations by our collaborator, Aurigene not only highlight our progress in immuno-oncology with CA-170, which we look to advance into the clinic in the first half of the year, but also Aurigene’s ability to extend the small molecule discovery capabilities to now target TIM3 in a separate program."

CUDC-907 presentation:

The Curis poster "Novel dual HDAC & PI3K inhibitor, CUDC-907, for MYC-driven malignancies" provided data on the activity of CUDC-907 in multiple MYC-altered disease models using both in vitro experiments and in vivo animal studies. Cell line and animal model studies using multiple MYC-altered DLBCL models showed that CUDC-907 had significant anti-tumor activity that correlated with the compound’s effect on downregulating MYC levels in a time and dose dependent manner. This effect was independent of disease subtypes classified using other molecular markers. CUDC-907 also showed potent anti-tumor activity in multiple cell lines of NUT midline carcinoma (NMC), a rare genetically defined tumor, which also demonstrates MYC dysregulation. CUDC-907 downregulated MYC levels in NMC cell lines and was more potent than BET inhibitors in in vitro assays of growth inhibition. The anti-tumor effects of CUDC-907 in NMC were further confirmed in a xenograft mouse model and in several MYC-amplified patient-derived xenograft models of solid tumors.

CA-170 (PD-L1/VISTA antagonist) and small molecule PD-L1/TIM-3 antagonist presentation:

The Aurigene presentation "Oral immune antagonist targeting PD-L1/VISTA or PD-L1/Tim3 for cancer therapy" provided data outlining the novel approach of identification and characterization of oral antagonists of immune checkpoint proteins. The lead IND-ready molecule, CA-170, targets PD-L1 and VISTA and has an optimized pharmacologic and safety profile required for human testing. Data from a second, independent program within the collaboration with compounds that target PD-L1 and TIM-3 immune checkpoints were also presented. In vitro studies showed that AUPM-327, a representative molecule from the PD-L1/TIM-3 program, can rescue T cell functions that are inhibited by addition of PD-L1 or TIM-3 checkpoint proteins, but does not affect other checkpoint regulators such as VISTA, CTLA4, and LAG-3, demonstrating its selectivity. Additionally, daily oral administration of the PD-L1/TIM-3 antagonist resulted in anti-tumor activity in multiple syngeneic tumor models including melanoma and colon cancer.

IRAK4 inhibitor presentation:

The Aurigene presentation "Efficacy and safety of highly selective novel IRAK4 inhibitors for treatment of ABC-DLBCL" provided a detailed profile of the pharmacologic and biologic properties of the lead molecule, CA-4948. This compound has favorable drug metabolism as well as pharmacokinetics properties and appears to have a clean in vitro toxicity profile. CA-4948 showed potent anti-tumor activity in vivo in two models of MYD88 mutant- DLBCL disease. CA-4948 also had potent anti-inflammatory effects in a rodent model of inflammation suggesting the potential use of an IRAK4 inhibitor in both cancer and inflammatory diseases.

Curis has exclusive licenses to CA-170 and CA-4948 under a collaboration agreement with Aurigene established in 2015.

Despite evidence for a role for prolactin signaling in breast and prostate tumorigenesis, a prolactin receptor-binding monoclonal antibody has not produced clinical efficacy.Increased serum prolactin levels may be a biomarker for prolactin receptor inhibition.Results from the pharmacokinetic and pharmacodynamics (PD) studies suggest that inappropriately long dosing intervals and insufficient exposure to LFA102 may have resulted in lack of antitumor efficacy.Based on preclinical data, combination therapy of LFA102 with those novel agents targeting hormonal pathways in metastatic castration-resistant prostate cancer and metastatic breast cancer is promising.Given the PD evidence of prolactin receptor blockade by LFA102, this drug has the potential to be used in conditions such as hyperprolactinemia that are associated with high prolactin levels.
Prolactin receptor (PRLR) signaling is implicated in breast and prostate cancer. LFA102, a humanized monoclonal antibody (mAb) that binds to and inhibits the PRLR, has exhibited promising preclinical antitumor activity.
Patients with PRLR-positive metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) received doses of LFA102 at 3-60 mg/kg intravenously once every 4 weeks. Objectives were to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) to investigate the safety/tolerability of LFA102 and to assess pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.
A total of 73 patients were enrolled at 5 dose levels. The MTD was not reached because of lack of dose-limiting toxicities. The RDE was established at 60 mg/kg based on PK and PD analysis and safety data. The most common all-cause adverse events (AEs) were fatigue (44%) and nausea (33%) regardless of relationship. Grade 3/4 AEs reported to be related to LFA102 occurred in 4% of patients. LFA102 exposure increased approximately dose proportionally across the doses tested. Serum prolactin levels increased in response to LFA102 administration, suggesting its potential as a biomarker for PRLR inhibition. No antitumor activity was detected.
Treatment with LFA102 was safe and well tolerated, but did not show antitumor activity as monotherapy at the doses tested.
©AlphaMed Press; the data published online to support this summary is the property of the authors.

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On April 20, 2016 Syros Pharmaceuticals reported that SY-1365, a first-in-class potent and selective cyclin-dependent kinase 7 (CDK7) inhibitor, was observed to induce durable tumor regression and prolong survival in in vivo models of acute myeloid leukemia (AML) (Press release, Syros Pharmaceuticals, APR 20, 2016, View Source [SID:1234511184]). These data were presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans. Based on the strong efficacy and safety data, Syros selected SY-1365 as its development candidate and plans to file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration in the second half of 2016 with the goal of initiating a Phase 1/2 clinical study in acute leukemia in the first half of 2017.

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"Up until now, creating medicines to control important disease causing transcription factors has been a major challenge in cancer drug development. SY-1365, our first-in-class CDK7 inhibitor, highlights the potential of our pioneering platform to produce drugs that can selectively modulate these transcription factors," said Nancy Simonian, M.D., Chief Executive of Syros. "Certain hematologic and solid tumor cancers, including AML, are dependent on transcription factors for their growth and survival and have been shown to be particularly dependent on CDK7. Results from preclinical studies demonstrate that SY- 1365 lowers the levels of these disease causing transcription factors and, in so doing, may treat diseases that have eluded other genomics-based approaches and provide a profound and durable benefit for patients with these difficult-to-treat cancers."

In the preclinical studies presented at AACR (Free AACR Whitepaper), SY-1365 was observed to preferentially kill cancer cells over non-cancerous cells and significantly prolong survival in patient-derived xenograft (PDX) models of AML. In the in vitro and in vivo studies, SY-1365 induced:

Tumor regression in 100 percent of treated mice in a cell-line derived xenograft model of AML; tumor regression was maintained through the end of the 38-day study.

Strong survival benefit, with 80 percent of treated mice alive at the end of the 8- week study in a PDX model of treatment-resistant AML; by contrast, none of the untreated mice survived beyond 4-1/2 weeks.

Rapid and dose-dependent apoptosis in AML cell lines treated with SY-1365 while having little to no effect on non-cancerous cells.
Potent and selective inhibition of CDK7, with only six other kinases, none of which are in the CDK family, exhibiting greater than 90 percent binding when profiled across a panel of 468 kinases at a concentration of 1μM.

Minimal effect on blood cell counts in in vivo models, including white blood cells, lymphocytes, neutrophils and reticulocytes, demonstrating a more favorable profile than a non-selective CDK inhibitor.

Reduced expression of cancer-contributing genes associated with specialized regulatory regions of DNA known as super-enhancers, including transcription factors and the oncogenes MYB and MYC, in an AML cell line.

Synergistic activity when combined with other targeted agents in AML, including Flt3, Bcl-2 and pan-Brd inhibitors.

Syros’ selective CDK7 inhibitors, including SY-1365, have been observed to delay tumor progression in additional in vivo models of transcriptionally addicted cancers, including acute lymphoblastic leukemia (ALL), MYCN-amplified neuroblastoma, small cell lung cancer and triple negative breast cancer.