On November 20, 2014 Blueprint Medicines disclosed a new drug discovery program targeting cancers with RET fusions and predicted resistance mutations (Press release, Blueprint Medicines, NOV 20, 2014, View Source [SID:1234508104]). The announcement was made during an oral presentation at the 26th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, on Blueprint Medicines’ discovery of several novel kinase fusions implicated in cancer and identification of several new cancer indications for known kinase fusions.
"One of the greatest challenges in treating cancer is addressing cancer cells’ ability to become resistant to therapy. Our new drug discovery program uniquely addresses both the activated wild-type form of RET and its predicted resistance mutations, enabling us to potentially develop a transformative therapy for cancer patients with RET fusions," said Christoph Lengauer, PhD, MBA, Chief Scientific Officer of Blueprint Medicines. "With the unveiling of this program, we add another proof point for the productivity of Blueprint Medicines’ team and the differentiation of its kinase-focused drug discovery platform, which combines an innovative target discovery engine with a first-of-its-kind fully-annotated chemical library."
Using proprietary computational tools and techniques, Blueprint Medicines’ scientists identified RET fusions in four of 20 cancer types analyzed, including thyroid, lung, breast and colon cancers, providing a strong rationale for the development of a novel RET inhibitor across multiple patient populations. The identification of RET fusions in colon and breast cancers was one of the novel findings in the research. Combining genomics with structural and cell biology, Blueprint Medicines’ scientists were able to predict future resistance mutations of RET inhibitors currently in clinical studies. Blueprint Medicines’ drug discovery is ongoing.
Blueprint Medicines’ new RET inhibitor program adds to the Company’s existing pipeline, consisting of BLU-285, the first known selective inhibitor of KIT Exon 17 for patients with systemic mastocytosis and gastrointestinal stromal tumors (GIST), and BLU-554, the first known selective FGFR4 inhibitor for patients with hepatocellular carcinoma (HCC). Blueprint Medicines expects to initiate clinical trials for its KIT and FGFR4 programs in 2015.
Fusion genes (or fusions) are known to contribute to the development of cancers. A fusion gene is formed from the abnormal association of two normally separated genes, as a result of a translocation or other chromosomal rearrangements. Fusion genes are proven cancer drug targets, and a number of approved and exploratory drugs target kinase fusions.

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On November 20, 2014 OncoSec Medical reported that it has entered into a Sponsored Research Agreement (SRA) with the University of Washington to evaluate the immunologic mechanisms of intratumoral DNA IL-12 electroporation (Press release OncoSec Medical, NOV 20, 2014, View Source [SID:1234500996]).

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Dr. I. Nicholas Crispe, MBBS, PhD, a professor in the Department of Immunology at the University of Washington and an expert in liver immunology and tolerance, will serve as the principal investigator. Using a novel liver cell isolation approach, Dr. Crispe has demonstrated that different types of liver cells have the capacity to present antigens, which likely contributes to hepatic immunosuppressive mechanisms. In this SRA, Dr. Crispe will apply these techniques to the B16 melanoma tumor model to not only better understand the systemic mechanisms of intratumoral DNA IL-12 electroporation (ImmunoPulse), but also to potentially identify other molecular targets that might combine with IL-12 to enhance immune response.

Dr. Robert H. Pierce, Chief Scientific Officer of OncoSec Medical, said, "We are excited to embark on this project with Dr. Crispe, who has tremendous expertise in mechanisms of immune tolerance. We believe he will bring fresh insights into tumor immuno-biology from his extensive knowledge of mechanisms of pathogen-induced immuno-subversion."

Dr. Crispe said, "We are focusing on taking the insights we have learned from studies of the basic biology of immune tolerance, and translating them directly to a model of human cancer. Although our initial target is malignant melanoma, we believe it is likely that data from these studies will be directly applicable to other cancers."

Interleukin-12 (IL-12) is a potent inflammatory cytokine that regulates multiple aspects of the immune system; in particular, it initiates both innate and adaptive immune responses. IL-12 is a key driver of the cascade of biological events that ultimately lead to T-cell-specific killing of cancer cells. Moreover, cytokines and chemokines induced by this pathway also increase the recruitment of inflammatory T-cells into tumors.

ImmunoPulse is a proprietary investigational electroporation device that delivers plasmid IL-12 DNA directly into tumors. By locally delivering and expressing IL-12, ImmunoPulse has shown in clinical studies to elicit anti-tumor immune activity, which has led not only to local tumor regression, but also to systemic anti-tumor regression, while mitigating toxicities typically observed with systemic administration of IL-12. Preliminary interim data from OncoSec’s ongoing Phase II study in melanoma provide evidence that local delivery of IL-12 by electroporation increases the production of cytokines such as IFN-γ, resulting in increased expression of genes related to the processes required for cytotoxic CD8+ T cells to recognize and kill cancer cells.

On November 20, 2014 Deciphera Pharmaceuticals reported the presentation of preclinical data which demonstrated that altiratinib (DCC-2701) provided balanced inhibition of MET, TRK, TIE2 and VEGFR2 kinases (Press release Deciphera Pharmaceuticals, NOV 20, 2014, View Source [SID:1234500992]). Altiratinib exhibited potency against both wild-type and mutant forms of MET and TRK kinases. In in vivo studies, altiratinib was shown to inhibit tumor growth, evasive vascularization, invasion and/or metastasis. In one model an increased overall survival was observed. Altiratinib exhibited anti-tumor activity in a variety of xenograft or allograft tumor models, including melanoma, gastric, lung, colorectal, breast, ovarian and glioblastoma. These data were presented today at the 26th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain. Altiratinib is currently in a Phase 1 clinical study in cancer patients with solid tumors.

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"In this preclinical data set, the profile observed with altiratinib demonstrated robust and durable inhibition of kinases related to multiple hallmarks of cancer., Our data demonstrate blocking of tumor progression and growth and tumor microenvironment related mechanisms, including evasive vascularization and metastasis in a variety of cancer models," said Michael D. Taylor, PhD, Deciphera’s President and Chief Executive Officer. "We look forward to further evaluation of altiratinib’s anti-cancer activity, including top-line data from our ongoing Phase 1 clinical study in patients with advanced solid tumors which is expected in mid-2015."

In a poster presentation titled "Altiratinib: a balanced inhibitor of MET, TRK, TIE2, and VEGFR2 kinases that exhibits broad anti-tumor and anti-angiogenic activities," Deciphera researchers described data which demonstrated that altiratinib inhibited tumors driven by MET amplification, overexpression, or mutation and also provided the potential for blocking tumor microenvironment angiogenic resistance mechanisms and pro-tumoral effects. Findings from the data include:

Altiratinib potently inhibited MET, TIE2, VEGFR2, and TRK kinases in functional cellular assays, including activity against proliferation, migration, and capillary tube formation, and with sufficient single-digit nanomolar potency such that all of these targets could be effectively inhibited simultaneously in vivo.
Altiratinib exhibited efficacy at preventing tumor growth, as well as inhibiting evasive vascularization, pro-tumoral macrophages, epithelial-to-mesenchymal transition (EMT) and metastasis in a variety of cancer models.
Altiratinib inhibited MET kinase for more than 24 hours after a single 10 mg/kg dose in a gastric cancer xenograft model leading to significant inhibition of tumor growth.
Altiratinib blocked bevacizumab-induced evasive vascularization and EMT in an aggressive, invasive glioblastoma model.
Altiratinib inhibited primary tumor growth and showed additive activity with paclitaxel; in addition, it reduced TIE2-expressing macrophages in the tumor stroma and significantly reduced lung metastases in a metastatic breast cancer model.
Altiratinib exhibited a long off-rate from kinases (greater than 24 hours from TIE2 and TRKA) in a variety of cell-based assays, based on its binding mode.
Altiratinib inhibited microvessel density and tumor growth in a xenograft model where both TIE2 and VEGFR2 kinases contribute to vessel growth.
Altiratinib compared favorably with other multi-targeted MET inhibitors, and had additional activity in inhibiting oncogenic MET mutants found in papillary renal cell carcinoma (PRCC), while other MET inhibitors have not been shown to inhibit activated MET mutants.

On November 20, 2014 Nektar Therapeutics reported results of a study investigating the preclinical anti-tumor activity and tolerability of etirinotecan pegol (NKTR-102) in combination with the PARP inhibitor rucaparib in a BRCA1-deficient MX-1 breast tumor model (Press release Nektar Therapeutics, NOV 20, 2014, View Source [SID:1234500995]). The preclinical study results demonstrated that all dose combinations of NKTR-102 and rucaparib were well-tolerated, synergistic, and led to 100% prolonged survival in this tumor model. These data were presented during the Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, sponsored by the European Organisation for Research and Treatment of Cancer (EORTC), the National Cancer Institute (NCI) and the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

"We are encouraged by these results which demonstrate that NKTR-102 in combination with the PARP inhibitor rucaparib has a synergistic effect resulting in 100% prolonged survival in a BRCA 1-deficient tumor model," said Stephen K. Doberstein, Ph.D., senior vice president and chief scientific officer of Nektar Therapeutics. "As a next-generation topo-I inhibitor with broad anti-tumor activity, NKTR-102 has the potential to be combined with a number of targeted agents in multiple tumor settings."

NKTR-102 is the first long-acting topoisomerase I inhibitor with an extended half-life and a unique structure that is also designed to concentrate the drug in tumors. In patients, NKTR-102 leads to greatly prolonged plasma SN38 exposure compared to irinotecan (elimination half-life of 50 days compared to 2 days) yet peak SN38 concentrations are at least 5- to 10-times less, which may also result in a favorable tolerability profile.

Preclinical Study Design and Results
Study investigators initiated tumor xenografts with MX-1 human breast carcinomas maintained by serial subcutaneous transplantation in female athymic nude (Crl:NU(Ncr)-Foxn1nu), 8-week-old mice. On the day of tumor implant, each test mouse received a 1-mm3 MX-1 fragment implanted subcutaneously in the right flank. Animals were randomized into treatment groups (n=10/grp) when their tumors reached 63-196 mm3 and subsequently received either vehicle, NKTR-102, rucaparab, or combinations of NKTR-102 + rucaparib. Doses selected were known to provide clinically relevant exposure levels. Twice weekly, animals were weighed, and tumor volumes were measured until the endpoint (2000 mm3 or Day 88) was met. Efficacy was measured by tumor growth delay and regression response rate.

NKTR-102 and rucaparib in combination exhibited marked synergy, demonstrated by durable complete responses, even at the lowest doses of both agents dosed in combination. The combination of NKTR-102 and rucaparib was tolerated at all dose levels. Doses used in this study provide exposures of NKTR-102 (SN38 trough) and rucaparib that are achievable clinically, underscoring the translational relevance of these results.

Combination studies of NKTR-102 and rucaparib are ongoing in patient-derived xenograft models in collaboration with Professor Paul Haluska at Mayo Clinic and Clovis Oncology.