On April 4, 2018 Genoscience Pharma, a clinical-stage biotechnology company dedicated to discovering and developing anticancer drugs, reported the first administration of GNS561 in a Phase 1/2a clinical study in advanced hepatocellular carcinoma (Press release, GenoScience, APR 5, 2018, View Source [SID1234525197]). This is the first clinical trial investigating this drug candidate, stemming from Genoscience Pharma’s research.

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This clinical research in liver cancer is led by Professor Ahmad Awada, head of medical oncology and principal investigator at the Jules Bordet Cancer Institute in Brussels, Belgium.

This international phase 1/2a study performed in Europe and the USA will evaluate safety, activity and the pharmacokinetics and pharmacodynamics of escalating doses of GNS561.

Up to 36 patients will be enrolled in six cohorts during the dose escalation phase. Additional patients will be enrolled in the continuation phase to obtain a total of 20 evaluable subjects at the recommended dose.

"This clinical program represents a paradigm shift for our company; it will provide a wealth of valuable additional knowledge and data to drive our platform of metal transporter modulators towards various clinical applications for cancer therapy," said Professor Philippe Halfon, president and CEO of Genoscience Pharma.

"Since being granted a rapid approval from regulatory authorities and institutional review boards, we have initiated the first-in-class GNS561 studies. The enrollment and treatment of the first patient represents a major milestone for Genoscience Pharma," said Professor Eric Raymond, chief medical officer.

"We are excited to be enrolling our first patient with GNS561. We are hopeful that this novel anticancer drug will prove to be a significant and effective weapon against liver cancer," said Pr. Ahmad Awada, principal investigator.
The study is run as an international clinical trial conducted in Europe and the USA. Professor Ghassan Abou Alfa at Memorial Sloan Kettering in New York is co-principal investigator.
His work focuses on preclinical and early-stage testing to optimize the development of stem cell-targeted cancer drugs.

About liver cancer
With more than 780,000 new cases diagnosed each year, liver cancer is the fifth most common cancer worldwide. It is the second leading cause of cancer-related deaths globally, accounting for approximately 746,000 deaths annually. The majority of liver cancers are detected at the advanced stage. New treatment options are urgently needed for these patients. HCC is the most common form of liver cancer, accounting for 90 percent of the worldwide total.

About GNS561
GNS561 is a novel Solute Carrier Transporter (SLCT) inhibitor demonstrating potent antitumor activity against a range of human cancer cell lines, including HCC. It also shows activity in cell lines resistant to current standard-of-care treatment options for HCC. GNS561 is an orally bioavailable compound initially being developed for the treatment of primary liver cancer, including advanced HCC. It is also being investigated preclinically in other solid tumors.

On April 5, 2018 Stemline Therapeutics, Inc. (Nasdaq:STML), a clinical-stage biopharmaceutical company developing novel oncology therapeutics, reported that it has initiated its rolling submission of a Biologics License Application (BLA) for SL-401 to the U.S. Food and Drug Administration (FDA) (Press release, Stemline Therapeutics, APR 5, 2018, View Source [SID1234532232]). SL-401 is a targeted therapy directed to CD123 that has been granted Breakthrough Therapy designation (BTD) by the FDA.

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Ivan Bergstein, MD, CEO of Stemline, commented, "The start of our rolling BLA submission is a major milestone for Stemline and the BPDCN patient community at large. If successful, SL-401 would be the first drug ever approved for BPDCN. Moreover, we believe that SL-401 may have a transformative impact on the outcomes of patients with this lethal malignancy of high unmet medical need. With this in mind, our clinical, regulatory, manufacturing, and commercial teams continue to work expeditiously to bring SL-401 to patients as quickly as possible."

On April 5, 2018 FORMA Therapeutics reported that it has successfully completed a critical objective under its strategic collaboration agreement with Celgene Corporation, triggering an undisclosed payment from Celgene (Press release, Forma Therapeutics, APR 5, 2018, View Source [SID1234525411]). Previously, FORMA and Celgene entered into a collaboration in the promising area of protein homeostasis to discover, develop and commercialize innovative drug candidates. This collaboration enables Celgene to evaluate select therapeutic candidates and programs in protein homeostasis during preclinical development.

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Jim Winkler, Ph.D., Vice President, Biology at FORMA Therapeutics said, "We are pleased with Celgene’s continued confidence in FORMA’s discovery research. This program represents a potential first-in-class therapeutic mechanism, by conferring both anti-tumor and immune-modulatory effects. We believe the field of protein homeostasis will deliver a promising pipeline of drugs, moving beyond cancer into immuno-oncology, inflammation and neurodegeneration."

About Protein Homeostasis
Protein homeostasis, which is important in oncology, neurodegenerative and other disorders, involves a tightly regulated network of pathways controlling the biogenesis, folding, transport and degradation of proteins. Exploring the maintenance and regulation of such competing, yet integrated, biological pathways using a chemical biology approach, should directly contribute to the understanding of diseases associated with excessive protein misfolding, aggregation and degradation.

On April 5, 2018 SignalRx Pharmaceuticals Inc., a clinical-stage company developing novel small-molecules therapeutics via in-silico design to simultaneously inhibit multiple key orthogonal and synergistic oncotargets for the treatment of cancer, reported the presentation of its novel triple CDK4-6/PI3K/BRD4 inhibitor program and first-in-class triple inhibitor SRX3177 (Press release, SignalRx, APR 5, 2018, http://www.ireachcontent.com/news-releases/signalrx-to-present-on-its-first-in-class-triple-cdk4-6pi3kbrd4-inhibitor-srx3177-for-treating-cancer-at-the-13th-annual-drug-discovery-chemistry-2018-meeting-678885923.html [SID1234527318]). The presentation by Donald L. Durden, MD, PhD, senior scientific advisor for SignalRx, will be at 2:20 pm on Thursday April 5th, 2018, in the Small Molecules for Cancer Immunotherapy session at the Drug Discovery Chemistry 2018 meeting in San Diego, CA. Data related to combinatorial small molecules which strike multiple immune-oncology cancer targets and activate the innate and adaptive anti-tumor immune response will be presented. The Small Molecules for Cancer Immunotherapy session will also be chaired by Dr. Durden.

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Using SignalRx’s proprietary CRIMP technology platform, the company designed SRX3177 to inhibit three key cancer-driving oncotargets with one drug: CDK4/6, PI3K and BRD4. SRX3177 results in synergistic synthetic lethality in cancer cells (e.g., breast cancer, mantle cell lymphoma) because this novel anticancer agent addresses the following critical cancer-driving facts:

PI3K inhibition abrogates resistance to CDK4/6 inhibition.
BRD4 inhibition decreases transcription of cyclin D1 and MYC.
MYC inhibition decreases levels of immuno-oncology targets CD47 and PD-L1.
CDK4/6 inhibition activates the AKT pathway.
"SignalRx designs all its novel chemotypes and drugs in silico. Because not a single chemotype comes from screening commercially available compounds, SignalRx has built and continues to build a strong and proprietary pipeline" said Dr. Donald L. Durden, founder and senior scientific advisor of SignalRx Pharmaceuticals and Professor and Associate Director of Pediatric Oncology at the Moores UCSD Cancer Center.

The profile of in silico designed small-molecule triple inhibitor SRX3177 includes:

Picomolar CDK4 inhibition potency.
Double-digit nM PI3K and BRD4 inhibitory potency.
BRD4-BD1 selective (5 X) vs BRD4-BD2.
5 Fold more potent than Palbociclib as CDK4 inhibitor.
19-80 Fold more potent than Palbociclib in 3 in vitro cancer cell assays.
40 Fold less toxic in normal epithelial cells vs corresponding combination of three separate inhibitors (Palbociclib + BKM120 + JQ1).
Induction of cell cycle arrest and increased apoptosis.
Lethal in 85% of the cancer cell lines tested in NCI 60 cancer-cell panel.
"All our chemotypes are small molecules (no linking moieties used). Because we rationally design all our anticancer agents from the beginning, we know how to tune in and out target affinity in our compounds. We are in an excellent position to also explore CDK4/6-BRD4 and CDK4/6-PI3K single small-molecule inhibitors for cancer and other applications" said Dr. Joseph Garlich, SignalRx’s Chief Scientific Officer.

SignalRx is also seeking partnering opportunities to accelerate the development of its programs and advance novel anticancer therapeutics into first-in-man clinical trials based on the promising profile and mode of action of its inhibitors. Since these are single molecules with a single PK/PD and toxicity profile, there is a great opportunity to streamline their development alone and in combination therapies.

On April 5, 2018 Oncoceutics, Inc. reported that the first patient has been treated in a clinical trial of ONC201 for patients with certain types of advanced endometrial and breast cancer (Press release, Oncoceutics, APR 5, 2018, View Source [SID1234558370]). The Phase II trial is led by Alexandra Zimmer, MD, Assistant Research Physician at the Women’s Malignancies Branch at the National Cancer Institute (NCI) Center for Cancer Research, part of the National Institutes of Health (NIH). The study will enroll up to 94 adult patients using ONC201 as a single-agent and will require tumor biopsies to enable direct evaluation of the activity of ONC201 within the tumor (Trials.cancer.gov Identifier#NCT03394027).

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Early results from ongoing clinical trials with ONC201 in high grade gliomas has shown promising single-agent activity that is related to the ability to target dopamine receptors. This study will extend the evaluation of ONC201 beyond glioma to include additional tumor types. This is the first clinical trial to launch out of a consortium of multiple investigators across different divisions at the NIH who are working with Oncoceutics to create, understand, and translate its novel class of therapies called imipridones to address unmet medical needs in oncology.

Endometrial and breast cancers have emerged as tumors that are sensitive to ONC201 in preclinical models through unique mechanisms of action that will be investigated in this clinical trial. Preclinical findings from a team of NCI investigators led by Stan Lipkowitz, MD, PhD, Chief of the Women’s Malignancies Branch in the NCI’s Center for Cancer Research, have shown that ONC201 has unique deleterious effects on the mitochondria of breast cancer cells. These findings are described in a recent publication (Greer et al., Oncotarget, In Press). This Phase II study continues the effort to understand the mechanism of ONC201, and to provide therapies to patients with metastatic breast cancer that are in need of new treatments.

Independent work led by Victoria Bae-Jump, MD, PhD, at UNC Lineberger Comprehensive Cancer Center, has found that dysregulated expression of dopamine receptors targeted by ONC201 induce tumor cell death in endometrial cancer. These findings were disclosed as an oral presentation at the recent annual meeting of the Society of Gynecological Oncology meeting in New Orleans.

"Unlike many other cancers, endometrial cancer has not gained targeted therapy treatment options despite the clear need for patients who have failed chemotherapy," said Dr. Bae-Jump. "Our recent work shows that endometrial cancer cells harbor altered expression of dopamine receptors that can be targeted by ONC201, creating the potential for an actionable molecular target for this disease."