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Hypoxia-inducible factor 1-mediated characteristic features of cancer cells for tumor radioresistance.

Tumor hypoxia has been attracting increasing attention in the fields of radiation biology and oncology since Thomlinson and Gray detected hypoxic cells in malignant solid tumors and showed that they exert a negative impact on the outcome of radiation therapy. This unfavorable influence has, at least partly, been attributed to cancer cells acquiring a radioresistant phenotype through the activation of the transcription factor, hypoxia-inducible factor 1 (HIF-1). On the other hand, accumulating evidence has recently revealed that, even though HIF-1 is recognized as an important regulator of cellular adaptive responses to hypoxia, it may not become active and induce tumor radioresistance under hypoxic conditions only. The mechanisms by which HIF-1 is activated in cancer cells not only under hypoxic conditions, but also under normoxic conditions, through cancer-specific genetic alterations and the resultant imbalance in intermediate metabolites have been summarized herein. The relevance of the HIF-1-mediated characteristic features of cancer cells, such as the production of antioxidants through reprogramming of the glucose metabolic pathway and cell cycle regulation, for tumor radioresistance has also been reviewed.
© The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

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An unbiased oncology compound screen to identify novel combination strategies.

Combination drug therapy is a widely used paradigm for managing numerous human malignancies. In cancer treatment, additive and/or synergistic drug combinations can convert weakly efficacious monotherapies into regimens that produce robust anti-tumor activity. This can be explained in part through pathway interdependencies that are critical for cancer cell proliferation and survival. However, identification of the various interdependencies is difficult due to the complex molecular circuitry that underlies tumor development and progression. Here, we present a high-throughput platform that allows for an unbiased identification of synergistic and efficacious drug combinations. In a screen of 22,737 experiments of 583 doublet combinations in 39 diverse cancer cell lines using a 4 by 4 dosing regimen, both well-known and novel synergistic and efficacious combinations were identified. Here, we present an example of one such novel combination, a Wee1 inhibitor (AZD1775) and an mTOR inhibitor (ridaforolimus), and demonstrate that the combination potently and synergistically inhibits cancer cell growth in vitro and in vivo. This approach has identified novel combinations that would be difficult to reliably predict based purely on our current understanding of cancer cell biology.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).

8-K – Current report

On March 18, 2016 Heat Biologics, Inc. ("Heat") (Nasdaq: HTBX), an immuno-oncology company developing novel therapies that activate a patient’s immune system against cancer, reported that it has priced an underwritten public offering of 9,100,000 shares of its common stock and warrants to purchase up to an aggregate of 6,825,000 shares of its common stock at a combined public offering price of $0.75 per share and related warrant (Filing, 8-K, Heat Biologics, MAR 18, 2016, View Source [SID:1234509646]). Each share of its common stock is being sold together with a warrant to purchase 0.75 of a share of its common stock. The gross proceeds from this offering to Heat are expected to be approximately $6.8 million, before deducting the underwriting discount and estimated offering expenses payable by Heat, but excluding the exercise of any warrants.

The shares of common stock will be immediately separable from the warrants and will be issued separately. The warrants are exercisable immediately upon issuance, expire five years after the date of issuance and have an exercise price of $1.00 per share. The warrants will be certificated and will be delivered to the investors by physical delivery following the closing. There is no established public trading market for the warrants and Heat does not expect a market to develop.

The offering is expected to close on or about March 23, 2016, subject to customary closing conditions.

Heat intends to use the net proceeds from the offering to complete its Phase 2 clinical trial evaluating HS-410 for the treatment of non-muscle invasive bladder cancer (NMIBC), which remains Heat’s primary focus. The remaining net proceeds will be used to advance the current eight patients enrolled in Heat’s Phase 1b clinical trial evaluating HS-110 for the treatment of non-small cell lung cancer (NSCLC) through the reporting of topline data, as well as for licensing or acquisition of assets complementary to its existing programs and for general corporate and working capital purposes.

Roth Capital Partners and Aegis Capital Corp. acted as joint book-running managers and Noble Financial Capital Markets acted as co-manager for this offering.

A registration statement on Form S-1 relating to the shares of common stock and warrants described above has been previously filed with and declared effective by the U.S. Securities and Exchange Commission (SEC). This offering is being made only by means of a prospectus forming a part of the effective registration statement. Copies of the final prospectus may be obtained from Roth Capital Partners, 888 San Clemente Drive, Suite 400, Newport Beach, CA 92660, Attention: Equity Capital Markets, or by telephone at 800-678-9147, or by email at [email protected], or from Aegis Capital Corp., 810 7th Avenue, 18th Floor, New York, NY 10019 or via telephone at 212-813-1010 or email at [email protected], or by accessing the SEC’s website at www.sec.gov.

This press release does not constitute an offer to sell or a solicitation of an offer to buy, nor shall there be any sale of these securities in any state or jurisdiction in which such an offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

The Myriad myRisk® Hereditary Cancer Test Identifies 60 Percent More Deleterious Mutations in Patients with Endometrial Cancer

On March 18, 2016 Myriad Genetics, Inc. (NASDAQ:MYGN), a leader in molecular diagnostics and personalized medicine, reported it will present two important new studies at the 2016 Society for Gynecologic Oncology annual meeting in San Diego, Calif (Press release, Myriad Genetics, MAR 18, 2016, View Source [SID:1234509630]).

The data demonstrate the ability of the myRisk Hereditary Cancer test to identify deleterious mutations in patients with endometrial cancer. Additionally, a different study showed the superior ability of the combined three biomarker myChoice HRD test to predict survival in patients with platinum treated ovarian cancer.

"Endometrial cancer is the most frequent gynecologic cancer and a significant number of these cases are due to mutations in hereditary cancer genes," said Johnathan Lancaster, M.D., Ph.D., chief medical officer, Myriad Genetic Laboratories. "Our new data show that gene panel testing can identify many more patients with harmful mutations than testing Lynch Syndrome genes alone. The additional information provided by the myRisk Hereditary Cancer test will help physicians optimize care for their patients."

Details about the featured Myriad presentations at SGO are below. Follow Myriad on Twitter via @MyriadGenetics and stay up-to-date with the meeting by using the hashtag #SGOMtg.

myRisk Hereditary Cancer Presentation — Endometrial Cancer

Title: Hereditary cancer panel testing in an unselected endometrial carcinoma cohort.
Date: Saturday, March 19, 2016: 7:50 to 9:55 a.m. PT.
Location: Podium — Abstract 6261.
Presenter: Kari Ring, MD Anderson Cancer Center.

This study evaluated the prevalence of cancer predisposition gene mutations in 381 endometrial cancer patients who had previously undergone tumor testing to screen for Lynch Syndrome. Patients were tested for mutations in 25 cancer genes using the myRisk Hereditary Cancer test. The results showed that 9.2 percent of endometrial cancer patients had a deleterious mutation, including 5.8 percent with a mutation in a Lynch Syndrome gene and 3.4 percent in 10 non-Lynch genes. Multi-gene panel testing with myRisk demonstrated the ability to identify 60 percent more mutations, several of which are associated with ovarian and uterine cancers. These findings support gene panel testing to identify patients who may be missed by current Lynch Syndrome testing alone.

myChoice HRD Presentation

Title: Homologous recombination deficiency (HRD) score shows superior association with outcome compared to its individual score components (LOH, TAI and LST) in platinum treated serous ovarian cancer.
Date: Saturday, March 19, 2016: 7:50 to 9:55 a.m. PT.
Location: Podium — Abstract 6286.
Presenter: Gordon B. Mills, M.D., Ph.D., MD Anderson Cancer Center.

This study compared the predictive ability of the combined three biomarker myChoice HRD score to the three independent measures of homologous recombination deficiency that comprise the assay including: loss of heterozygosity (LOH) score, telomeric-allelic imbalance (TAI) score, and large-scale state transitions (LST) score. The results showed that the combined myChoice HRD score predicted progression-free survival (p=2.2×10-6) and overall survival (p=1.0×10-8) in patients with platinum-treated ovarian cancer. In a bivariate analysis none of the individual biomarkers (LOH, TAI and LST) reached statistical significance for either progression free survival or overall survival. In this study, myChoice HRD was shown to be a superior predictor of clinical outcomes to any of the individual score components including LOH, TAI and LST.

About Myriad myRisk Hereditary Cancer Testing
The Myriad myRisk Hereditary Cancer test uses next-generation sequencing technology to evaluate 25 clinically significant genes associated with eight hereditary cancer sites including: breast, colon, ovarian, endometrial, pancreatic, prostate and gastric cancers and melanoma. For more information visit: myriad.com.

About myChoice HRD
Myriad’s myChoice HRD is the first homologous recombination deficiency test that can detect when a tumor has lost the ability to repair double-stranded DNA breaks, resulting in increased susceptibility to DNA-damaging drugs such as platinum drugs or PARP inhibitors. High myChoice HRD scores reflective of DNA repair deficiencies are prevalent in all breast cancer subtypes, ovarian and most other major cancers. In previously published data, Myriad showed that the myChoice HRD test predicted drug response to platinum therapy in certain patients with triple-negative breast and ovarian cancers. It is estimated that 1.8 million people in the United States and Europe who are diagnosed with cancers annually may be candidates for treatment with DNA-damaging agents. For more information visit: myriad.com.

Alligator presents at Carnegie Healthcare Seminar

On March 17, 2016 Alligator presented the corporate presentation (Presentation, Alligator Bioscience, MAR 17, 2016, View Source [SID1234538697]).