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Design, synthesis and structure activity relationship of potent pan-PIM kinase inhibitors derived from the pyridyl carboxamide scaffold.

The Pim proteins (1, 2 and 3) are serine/threonine kinases that have been found to be upregulated in many hematological malignancies and solid tumors. As a result of overlapping functions among the three isoforms, inhibition of all three Pim kinases has become an attractive strategy for cancer therapy. Herein we describe our efforts in identifying potent pan-PIM inhibitors that are derived from our previously reported pyridyl carboxamide scaffold as part of a medicinal chemistry strategy to address metabolic stability.
Copyright © 2016 Elsevier Ltd. All rights reserved.

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Promises and pitfalls for recombinant oligoclonal antibodies-based therapeutics in cancer and infectious disease.

Monoclonal antibodies (mAbs) have revolutionized the diagnosis and treatment of many human diseases and the application of combinations of mAbs has demonstrated improved therapeutic activity in both preclinical and clinical testing. Combinations of antibodies have several advantages such as the capacities to target multiple and mutating antigens in complex pathogens and to engage varied epitopes on multiple disease-related antigens (e.g. receptors) to overcome heterogeneity and plasticity. Oligoclonal antibodies are an emerging therapeutic format in which a novel antibody combination is developed as a single drug product. Here, we will provide historical context on the use of oligoclonal antibodies in oncology and infectious diseases and will highlight practical considerations related to their preclinical and clinical development programs.
Copyright © 2016 Elsevier Ltd. All rights reserved.

Treatment of experimental human breast cancer and lung cancer brain metastases in mice by macitentan, a dual antagonist of endothelin receptors, combined with paclitaxel.

We recently demonstrated that brain endothelial cells and astrocytes protect cancer cells from chemotherapy through an endothelin-dependent signaling mechanism. Here, we evaluated the efficacy of macitentan, a dual endothelin receptor (ETAR and ETBR) antagonist, in the treatment of experimental breast and lung cancer brain metastases.
The effect of macitentan on astrocyte- and brain endothelial cell-mediated chemoprotective properties was measured in cytotoxic assays. We compared survival of mice bearing established MDA-MB-231 breast cancer or PC-14 non-small cell lung cancer (NSCLC) brain metastases that were treated with vehicle, macitentan, paclitaxel, or macitentan plus paclitaxel. Cell division, apoptosis, tumor vasculature, and expression of survival-related proteins were assessed by immunofluorescent microscopy.
Cancer cells and tumor-associated endothelial cells expressed activated forms of AKT and MAPK in vehicle- and paclitaxel-treated groups in both metastasis models, but these proteins were downregulated in metastases of mice that received macitentan. The survival-related proteins Bcl2L1, Gsta5, and Twist1 that localized to cancer cells and tumor-associated endothelial cells in vehicle- and paclitaxel-treated tumors were suppressed by macitentan. Macitentan or paclitaxel alone had no effect on survival. However, when macitentan was combined with paclitaxel, we noted a significant reduction in cancer cell division and marked apoptosis of both cancer cells and tumor-associated endothelial cells. Moreover, macitentan plus paclitaxel therapy significantly increased overall survival by producing complete responses in 35 of 35 mice harboring brain metastases.
Dual antagonism of ETAR and ETBR signaling sensitizes experimental brain metastases to paclitaxel and may represent a new therapeutic option for patients with brain metastases.
© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Virogin Biotech announced the completion of the US$ 7 million of financing

On March 21, 2016 Virogin Biotech reported the completion of A-round common share financing for a total of $7 million (USD) on March 16th 2016 (Press release, Virogin Biotech, MAR 21, 2016, View Source [SID1234518862]).

Virogin Biotech Ltd. specializes in anti-cancer drug research with a focus on innovative anti-cancer vaccines through the use of oncolytic viruses carrying immune stimulating factors. The financing was led by GP Capital Investment Fund with co-investors Shen Zhen Sangel Asset Management Ltd, Purity Star Ltd, Dahua Investment Company and Top Fortune Ventures Ltd, wherein GP Capital and Shen Zhen Sangel were the angel investors of Virogin, and Purity Star, Dahua and Top Fortune Ventures are new investors. The continued financial support of previous investors, alongside new entrants, reflects investor confidence in Virogin’s continuing development.

Virogin is planning to use the proceeds in three areas: the completion of pre-clinical research for our next generation oncolytic virus, expanding our global clinical development team and its capabilities, and enhancing our production capacity to meet clinical needs.

Virogin’s co-founder and CSO Dr. William Jia said: "Virogin’s novel oncolytic virus products represent the next generation of oncolytic viruses, which are enhanced both in oncolytic activity and tumor specificity. At present, Virogin’s product line has progressed smoothly and since June of last year, Virogin has applied for several U.S. Patents. The success of A-round financing ensures Virogin’s momentum for high-speed development and helps to accelerate our products into clinical trials. "

"We are pleased with the continued support from our angel investors; moreover, we are appreciative for the support from our new investors, who include the founders of a listed large-cap company and the founder of an investment fund in the vaccine industry" said Mr. Chris Huang, co-founder and CEO of Virogin. "To bring renewed hope to millions of helpless cancer patients with innovative anti-tumor immunotherapy is Virogin’s dream, and this dream is shared by our investors. We are confident that in the near future we will bring our first oncolytic virus product to phase I clinical trials."

GP Capital Investment Fund founder and president Dongmei Ji said, "We witnessed the establishment of Virogin. It is a wonderful experience to accompany the growth of a company. In this process, you can feel the passion and unlimited vitality of a company. As fund managers, we are pleased to allocate our funds and resources to a promising company with a good research team and technology like Virogin."

Dr. Fangfeng, a partner in Sangel Capital said: "Immunotherapy is the future direction of anti-tumor development; from the very beginning, we are confident in Virogin’s cutting edge technology and the ability of Virogin’s science team. We are very pleased with Virogin’s rapid growth and we will continue to support Virogin in developing its innovative anti-tumor immunology drug."

6-K – Report of foreign issuer [Rules 13a-16 and 15d-16]

On March 21, 2016 Oncolytics Biotech Inc. (TSX: ONC) (OTCQX: ONCYF) (FRA: ONY) ("Oncolytics" or the "Company") reported an update for a randomized Phase II clinical trial of its lead product, REOLYSIN, in combination with paclitaxel in patients with ovarian cancer (GOG-0186H) (Filing, 6-K, Oncolytics Biotech, MAR 21, 2016, View Source [SID:1234509813]).

The study is being sponsored by the US National Cancer Institute ("NCI"). The update includes data from a Gynecologic Oncology Group (GOG) study summary report, and follows a presentation made by the principal investigator regarding the study at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer, which runs from March 19-22 in San Diego, CA.

Update Highlights

Response Using CA-125 Measurements by Treatment Among all Patients

CA-125 Response Treatment
Paclitaxel Paclitaxel+REOLYSIN Total
Full Response 1 (1.85%) 5 (9.26%) 6
Partial Response 9 (16.67%) 7 (12.96%) 16
Stable Disease 3 (5.56%) 12 (22.22%) 15
Progressive Disease 0 (0.00%) 2 (3.70%) 2
Indeterminate 16 (29.63%) 13 (24.07%) 29
Not Evaluable 25 (46.30%) 15 (27.78%) 40
Total 54 54 108
Source: GOG Study Summary Report

The Company performed an intent-to-treat analysis of tumour response, as assessed by CA-125 antigen levels, which showed statistically significantly higher full response rates and stable disease or better rates in the test arm versus the control arm. The rate of full responses in the test arm was 9.26%, compared with 1.85% in the control arm (p = 0.0196). The rate of stable disease or better in the test arm was 44.44%, compared with 24.08% in the control arm (p = 0.0096). The response rates were defined using a modified Rustin’s criteria. CA-125 levels are commonly used in clinical practice to assess response in ovarian cancer patients.

Response rates as measured by RECIST were performed on patients with measurable disease (n = 68 (of 108)). The proportion responding on the test arm was 17% whereas the proportion responding on the control arm was 20%.

An analysis of progression free survival ("PFS") stratified by measurable disease and platinum-free interval (test arm: n = 54, 43 events (progressions), and control arm: n = 54, 48 events) was performed and demonstrated a median PFS of 4.4 months for the test arm, and 4.3 months for the control arm.

An interim analysis of overall survival ("OS") (test arm: n = 54, 32 events (deaths), and control arm: n = 54, 32 events) was performed and demonstrated a median OS of 12.9 months for the test arm, and 15.0 months for the control arm. The OS was an interim analysis, as 44 (41%) patients out of a total of 108 patients were alive at the time of analysis. Given the number of patients still alive on the test and control arms with current survival less than the median, final median OS results are expected to change.

"This is one of a total of six randomized Phase II studies with REOLYSIN that were designed and sponsored by third parties. The results from these studies will determine clinical targets, endpoints, and study designs for follow on and registration studies conducted by Oncolytics. In the case of this ovarian cancer study, we are pleased that REOLYSIN has demonstrated a statistically significant reduction in tumour burden in ovarian cancer patients as measured by CA-125 levels," said Dr. Brad Thompson, President and CEO of Oncolytics. "This adds to our results in other indications that have shown improvement in tumour responses. In order to further our understanding of how REOLYSIN interacts with the immune system, we hope, in conjunction with the principal investigator, to analyze the PD-1 and CD8+ T lymphocyte levels of patients on entry and correlate these with overall survival and progression free survival."

Study Design Summary
The study (GOG-0186H) is a randomized Phase 2 clinical trial of paclitaxel versus paclitaxel plus REOLYSIN in patients with persistent or recurrent, ovarian, fallopian tube or primary peritoneal cancer. Patients received paclitaxel on days 1, 8 and 15 of each 28-day treatment cycle, with either REOLYSIN (test arm) or placebo (control arm) administered on days 1 through 5. One hundred and eight patients were randomized (1:1, 54 patients in the control arm, 54 patients in the test arm). The NCI study did not stratify on entry according to PD-L1 levels or infiltrating CD8+ T lymphocyte levels, nor were either of those levels measured post-treatment. However, pre-treatment tumour biopsies were taken from the majority of patients. The primary objectives are PFS and toxicity. The secondary objectives are median overall OS by treatment group, median PFS by treatment group, and tumour response as measured by RECIST criteria and CA-125 antigen levels. The study was sponsored by the US National Cancer Institute and conducted by the former GOG, now incorporated into NRG Oncology.

Analysis of the Relationship between Ovarian Cancer Patients’ Immune Status upon Study Entry and Survival
In order to further understand the effects of a patient’s immune status prior to treatment with REOLYSIN on PFS and OS, the principal investigator and the Company are working to quantify the levels of PD-L1 and CD8+ T lymphocytes in tumours at the time of enrolment. The Company wishes to conduct this analysis to be able to determine what component of PFS and OS is attributable to PD-L1 and CD8+ T lymphocyte levels on study entry, and what is attributable to REOLYSIN therapy.

The basis for this analysis is Hamanishi et al. (2007) (Programmed cell death 1 ligand 1 and tumour-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. PNAS 104(9):3360-3365), which found that the overall survival rates and progression free survival rates for ovarian cancer patients with high PD-L1 expression on entry were statistically significantly worse than those of patients with low PD-L1 expression on entry. They also noted that the overall survival rates and progression free survival rates for ovarian cancer patients with high intraepithelial CD8+ T lymphocyte counts on entry were statistically significantly better than those of patients with low CD8+ T lymphocyte counts.