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DelMar Pharmaceuticals Announces Abstract Presentations for the American Association Cancer Research (AACR) Annual Meeting in April 2016

On March 24, 2016 DelMar Pharmaceuticals, Inc. (OTCQX: DMPI) ("DelMar" and the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported that it will present three abstracts at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting based on pre-clinical research conducted with its lead anti-cancer product candidate, VAL-083 (dianhydrogalactitol), a "first-in-class" small-molecule chemotherapeutic agent (Press release, DelMar Pharmaceuticals, MAR 24, 2016, View Source [SID:1234509928]).

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The Company’s first two abstracts have been published and can be viewed on the AACR (Free AACR Whitepaper) Annual Meeting website.

DelMar will present abstract (#2157): "Enhanced in vitro activity of dianhydrogalactitol (VAL-083) in combination with platinum drugs: Impact of p53 and platinum-resistance," during the session entitled "New Drugs, Therapeutic Targets, and Treatment Approaches being held on Monday, April 18, 2016, from 1:00 p.m.-5:00 p.m. CDT. In this abstract, the Company will present new in vitro data in cell-lines representing difficult to treat subsets of non-small cell lung and ovarian cancer that may be targeted by VAL-083’s unique anti-cancer mechanism.

A second abstract (#2985): "Molecular mechanisms of dianhydrogalactitol (VAL-083) in cancer treatment," will be presented during the session entitled New Mechanisms of Anticancer Drug Action being held on Tuesday, April 19, 2016, from 8:00 a.m.-12:00 p.m. CDT. In this abstract, DelMar will present new data related to VAL-083’s mechanism of action, which may lead to opportunities to treat resistant cancer phenotypes and to beneficial combination therapy approaches in the treatment of cancer.

DelMar will also present an update on its ongoing "Phase I/II study of VAL-083 in patients with recurrent glioblastoma," as a late-breaking abstraction during the Phase II/III Clinical Trials in Progress session on Tuesday, April 19. Details of this abstract (#CT074) will be published during the session beginning at 8:00 a.m. CDT.

About VAL-083
VAL-083 is a "first-in-class," small-molecule chemotherapeutic. In more than 40 Phase I and II clinical studies sponsored by the U.S. National Cancer Institute, VAL-083 demonstrated clinical activity against a range of cancers including lung, brain, cervical, ovarian tumors and leukemia both as a single-agent and in combination with other treatments. VAL-083 is approved in China for the treatment of chronic myelogenous leukemia (CML) and lung cancer, and has received orphan drug designation in Europe and the U.S. for the treatment of malignant gliomas. DelMar recently announced that the FDA’s Office of Orphan Products had also granted an orphan designation to VAL-083 for the treatment of medulloblastoma.

DelMar has demonstrated that VAL-083’s anti-tumor activity is unaffected by the expression of MGMT, a DNA repair enzyme that is implicated in chemotherapy resistance and poor outcomes in GBM patients following standard front-line treatment with Temodar (temozolomide).

DelMar has been conducting a Phase I/II clinical trial in GBM patients whose tumors have progressed following standard treatment with temozolomide, radiotherapy, bevacizumab and a range of salvage therapies.

Sub-group analysis of data from the Phase I dose-escalation portion of the study suggests a dose-dependent and clinically meaningful survival benefit following treatment with VAL-083. Patients in a low dose (≤5mg/m2) sub-group had a median survival of approximately five (5) months versus median survival of approximately nine (9) months for patients in the therapeutic dose (30mg/m2 & 40mg/m2) sub-group following initiation of VAL-083 treatment. DelMar also reported increased survival at 6, 9 and 12 months following initiation of treatment with VAL-083 in the therapeutic dose sub-group compared to the low dose sub-group.

VAL-083 is well tolerated using a regimen of 40mg/m2 daily x 3 every 21 days. Dose limiting toxicity (DLT) defined by thrombocytopenia (low platelet counts) was observed at doses above 40 mg/m2. Generally, DLT-related symptoms resolved rapidly and spontaneously without concomitant treatment.

Based on these data, DelMar initiated a Phase II expansion cohort utilizing the 40mg/m2 dosing regimen in June 2015 at five clinical centers in the United States: Mayo Clinic (Rochester, MN); UCSF (San Francisco, CA) and three centers associated with the Sarah Cannon Cancer Research Institute (Nashville, TN, Sarasota, FL and Denver, CO). DelMar announced the completion of enrollment in a Phase II expansion cohort in September, 2015.

Further details can be found at View Source

The production of coagulation factor VII by adipocytes is enhanced by tumor necrosis factor-α or isoproterenol.

A relationship has been reported between blood concentrations of coagulation factor VII (FVII) and obesity. In addition to its role in coagulation, FVII has been shown to inhibit insulin signals in adipocytes. However, the production of FVII by adipocytes remains unclear.
We herein investigated the production and secretion of FVII by adipocytes, especially in relation to obesity-related conditions including adipose inflammation and sympathetic nerve activation.
C57Bl/6J mice were fed a low- or high-fat diet and the expression of FVII messenger RNA (mRNA) was then examined in adipose tissue. 3T3-L1 cells were used as an adipocyte model for in vitro experiments in which these cells were treated with tumor necrosis factor-α (TNF-α) or isoproterenol. The expression and secretion of FVII were assessed by quantitative real-time PCR, Western blotting and enzyme-linked immunosorbent assays.
The expression of FVII mRNA in the adipose tissue of mice fed with high-fat diet was significantly higher than that in mice fed with low-fat diet. Expression of the FVII gene and protein was induced during adipogenesis and maintained in mature adipocytes. The expression and secretion of FVII mRNA were increased in the culture medium of 3T3-L1 adipocytes treated with TNF-α, and these effects were blocked when these cells were exposed to inhibitors of mitogen-activated kinases or NF-κB activation. The β-adrenoceptor agonist isoproterenol stimulated the secretion of FVII from mature adipocytes via the cyclic AMP/protein kinase A pathway. Blockade of secreted FVII with the anti-FVII antibody did not affect the phosphorylation of Akt in the isoproterenol-stimulated adipocytes.
Obese adipose tissue produced FVII. The production and secretion of FVII by adipocytes was enhanced by TNF-α or isoproterenol via different mechanisms. These results indicate that FVII is an adipokine that plays an important role in the pathogenesis of obesity.

Crucial roles of XCR1-expressing dendritic cells and the XCR1-XCL1 chemokine axis in intestinal immune homeostasis.

Intestinal immune homeostasis requires dynamic crosstalk between innate and adaptive immune cells. Dendritic cells (DCs) exist as multiple phenotypically and functionally distinct sub-populations within tissues, where they initiate immune responses and promote homeostasis. In the gut, there exists a minor DC subset defined as CD103(+)CD11b(-) that also expresses the chemokine receptor XCR1. In other tissues, XCR1(+) DCs cross-present antigen and contribute to immunity against viruses and cancer, however the roles of XCR1(+) DCs and XCR1 in the intestine are unknown. We showed that mice lacking XCR1(+) DCs are specifically deficient in intraepithelial and lamina propria (LP) T cell populations, with remaining T cells exhibiting an atypical phenotype and being prone to death, and are also more susceptible to chemically-induced colitis. Mice deficient in either XCR1 or its ligand, XCL1, similarly possess diminished intestinal T cell populations, and an accumulation of XCR1(+) DCs in the gut. Combined with transcriptome and surface marker expression analysis, these observations lead us to hypothesise that T cell-derived XCL1 facilitates intestinal XCR1(+) DC activation and migration, and that XCR1(+) DCs in turn provide support for T cell survival and function. Thus XCR1(+) DCs and the XCR1/XCL1 chemokine axis have previously-unappreciated roles in intestinal immune homeostasis.

HepaRG culture in tethered spheroids as an in vitro three-dimensional model for drug safety screening.

Conventional two-dimensional (2D) monolayer cultures of HepaRG cells allow in vitro maintenance of many liver-specific functions. However, cellular dedifferentiation and functional deterioration over an extended culture period in the conventional 2D HepaRG culture have hampered its applications in drug testing. To address this issue, we developed tethered spheroids of HepaRG cells on Arg-Gly-Asp (RGD) and galactose-conjugated substratum with an optimized hybrid ratio as an in vitro three-dimensional (3D) human hepatocyte model. The liver-specific gene expression level and drug metabolizing enzyme activities in HepaRG-tethered spheorids were markedly higher than those in 2D cultures throughout the culture period of 7 days. The inducibility of three major cytochrome P450 (CYP) enzymes, namely CYP1A2, CYP2B6 and CYP3A4, was improved in both mRNA and activity level in tethered spheroids. Drug-induced cytotoxic responses to model hepatotoxins (acetaminophen, chlorpromazine and ketoconazole) in tethered spheroids were comparable to 2D cultures as well as other studies in the literature. Our results suggested that the HepaRG-tethered spheroid would be an alternative in vitro model suitable for drug safety screening.
Copyright © 2014 John Wiley &amp; Sons, Ltd.

Merck Foundation Awards Grant to American Cancer Society for Program to Improve Access to High-Quality Cancer Care in Underserved Communities

On March 24, 2016 The Merck Foundation (the Foundation) and the American Cancer Society (ACS) reported that the Foundation provided a grant of $1.58 million over four years to the ACS to implement a comprehensive Patient Navigation Program in three U.S. communities where substantial cancer care disparities exist (Press release, Merck & Co, MAR 24, 2016, View Source [SID:1234509919]). This funding will allow the ACS to enhance its already substantial Patient Navigation Program and expand its focus on access to high-quality care, patient empowerment and care coordination.

Sites selected to participate in the community-based program include the Queens Hospital Center in Queens, N.Y.; the Phoenix Cancer Center/Maricopa Integrated Health System in Phoenix; and the University of New Mexico Cancer Center in Albuquerque, N.M. The organizations were selected because they provide services to diverse, low-income and often underserved patient populations.

"For 125 years, Merck has focused on finding solutions to improve care for patients facing devastating diseases like cancer," said Brenda D. Colatrella, president, Merck Foundation and executive director, Corporate Responsibility, Merck. "Receiving a cancer diagnosis can be an overwhelming experience, and we are proud to work with the American Cancer Society to help empower those touched by cancer to navigate the often complicated path to finding the best care available."

"Many people don’t know how to access the health care system. They don’t have insurance, they’re afraid or they have personal beliefs that lead them to ignore their health and avoid the health care system altogether," said Katherine Sharpe, senior vice president, Patient and Caregiver Support, American Cancer Society. "The Patient Navigation Program addresses these issues and helps people get the care they need even under very difficult cultural, economic, educational and financial circumstances. At the heart of patient navigation is the lesson that offering an ear to listen and a hand to help can have remarkable impact on the health of those most in need. We are grateful to the Merck Foundation for providing this grant to bring much-needed support to cancer patients in vulnerable communities in Arizona, New Mexico and New York."

The Patient Navigation Program is a proactive approach to providing guidance and support for cancer patients, their families and caregivers. Currently, more than 100 Patient Navigators are working in hospitals and cancer treatment centers nationwide. They help with identifying and reducing barriers to treatment, such as challenges with language, transportation and health insurance. In 2015, the Patient Navigation Program provided services to more than 44,000 patients across the nation, more than one-third of whom were covered by Medicaid or were uninsured.

About the American Cancer Society

The American Cancer Society is a global grassroots force of 2.5 million volunteers saving lives and fighting for every birthday threatened by every cancer in every community. As the largest voluntary health organization, the Society’s efforts have contributed to a 22 percent decline in cancer death rates in the U.S. since 1991, and a 50 percent drop in smoking rates. Thanks in part to our progress,14.5 million Americans who have had cancer and countless more who have avoided it will celebrate more birthdays this year. We’re determined to finish the fight against cancer. We’re finding cures as the nation’s largest private, not-for-profit investor in cancer research, ensuring people facing cancer have the help they need and continuing the fight for access to quality health care, lifesaving screenings, clean air and more. For more information, to get help, or to join the fight, call us anytime, day or night, at (800) 227-2345 or visit cancer.org.