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Mancini M.L.,Beth Israel Deaconess Medical Center | Mancini M.L.,Champions Oncology | Lien E.C.,Beth Israel Deaconess Medical Center | Toker A.,Beth Israel Deaconess Medical Center
Oncotarget | Year: 2016

One of the most frequently deregulated signaling pathways in breast cancer is the PI 3-K/Akt cascade. Genetic lesions are commonly found in PIK3CA, PTEN, and AKT, which lead to excessive and constitutive activation of Akt and downstream signaling that results in uncontrolled proliferation and increased cellular survival. One such genetic lesion is the somatic AKT1(E17K) mutation, which has been identified in 4-8% of breast cancer patients. To determine how this mutation contributes to mammary tumorigenesis, we constructed a genetically engineered mouse model that conditionally expresses human AKT1(E17K) in the mammary epithelium. Although AKT1(E17K) is only weakly constitutively active and does not promote proliferation in vitro, it is capable of escaping negative feedback inhibition to exhibit sustained signaling dynamics in vitro. Consistently, both virgin and multiparous AKT1(E17K) mice develop mammary gland hyperplasia that do not progress to carcinoma. This hyperplasia is accompanied by increased estrogen receptor expression, although exposure of the mice to estrogen does not promote tumor development. Moreover, AKT1(E17K) prevents HER2-driven mammary tumor formation, in part through negative feedback inhibition of RTK signaling. Analysis of TCGA breast cancer data revealed that the mRNA expression, total protein levels, and phosphorylation of various RTKs are decreased in human tumors harboring AKT1(E17K).

Garralda E.,Spanish National Cancer Research Center | Paz K.,Hospital Universitario Madrid Sanchinarro | Lopez-Casas P.P.,Spanish National Cancer Research Center | Jones S.,Hospital Universitario Madrid Sanchinarro | And 14 more authors.
Clinical Cancer Research | Year: 2014

Background: Current technology permits anunbiasedmassive analysis of somatic genetic alterations from tumorDNA aswell as the generation of individualizedmouse xenografts (Avatarmodels). Thiswork aimed to evaluate our experience integrating these two strategies to personalize the treatment of patients with cancer. Methods: We performed whole-exome sequencing analysis of 25 patients with advanced solid tumors to identify putatively actionable tumor-specific genomic alterations. Avatar models were used as an in vivo platform to test proposed treatment strategies. Results: Successful exome sequencing analyses have been obtained for 23 patients. Tumor-specific mutations and copy-number variations were identified. All samples profiled contained relevant genomic alterations. Tumor was implanted to create an Avatar model from 14 patients and 10 succeeded. Occasionally, actionable alterations such as mutations in NF1, PI3KA, and DDR2 failed to provide any benefit when a targeted drug was tested in the Avatar and, accordingly, treatment of the patients with these drugs was not effective. To date, 13 patients have received a personalized treatment and 6 achieved durable partial remissions. Prior testing of candidate treatments in Avatar models correlated with clinical response and helped to select empirical treatments in some patients with no actionable mutations. Conclusion: The use of full genomic analysis for cancer care is encouraging but presents important challenges that will need to be solved for broad clinical application. Avatar models are a promising investigational platform for therapeutic decision making. While limitations still exist, this strategy should be further tested. © 2014 AACR.

Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer and the second leading cause of cancer deaths in the United States. More than 50,000 people die of CRC each year and almost half of all newly diagnosed patients are in an advanced stage of cancer (metastatic CRC) when they are first diagnosed. Because of the relatively low response rates of cancer patients to different drug regimens, researchers with InSilico Medicine and Champions Oncology set out to find biological signals or biomarkers in cancerous tumors that might predict in advance whether a patient is likely to respond to a drug treatment. Researchers focused on cetuximab, which is an antibody used in the targeted treatment of CRC patients who do not have a mutation of the K-ras gene. Yet, despite its approval by the FDA for use in these patients, cetuximab is successful in 40 to 60% of these cases. According to a joint paper just released by Champions Oncology and InSilico Medicine, the two companies have identified a biological indicator that may predict in advance the likelihood that a specific patient will respond to cetuximab. If validated through clinical trials, researchers believe this “green light” tool will help oncologists make better decisions for patients. “We're thrilled to collaborate with Champions Oncology and Dr. David Sidransky at Johns Hopkins University. While Champions is the leader in personalized medicine, we specialize in big data analysis and signaling pathway analysis. Working together, we're the most promising competitor in personalized medicine,” said Alex Zhavoronkov, PhD, CEO of InSilico Medicine, Inc. “Utilizing our TumorGraft platform and signaling pathway analysis from InSilico Medicine, we may decipher pathway activation profiles in cancer patients that lead to a better personalized treatment,” said Keren Paz, PhD, Chief Scientific Office at Champions Oncology Inc. About InSilico Medicine InSilico Medicine, Inc. is a Baltimore-based company utilizing advances in genomics and big data analysis for in silico drug discovery and drug repurposing for aging and age-related diseases. The company utilizes the GeroScope™, OncoFinder™ , Pathway Cloud Intelligence™ and PharmAtlas™ packages for aging and cancer research, pursues internal drug discovery programs, and provides services to pharmaceutical companies. If you have any questions about the science of aging, bioinformatics, or InSilico Medicine's plan in anti-aging research and drug discovery, please call (443) 451- 7212 or visit: http://www.insilicomedicine.com.

News Article | February 13, 2014
Site: www.bloomberg.com

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HOLLISTON, Mass.--(BUSINESS WIRE)--Harvard Apparatus Regenerative Technology, Inc. (Nasdaq: HART), or HART, a biotechnology company developing bioengineered organs for clinical use, today announced the appointment of James McGorry, MBA, as Chief Executive Officer, effective July 6, 2015. Mr. McGorry has more than 25 years of experience as a life science business leader in biologics, personalized medicine and medical devices, including multiple product launches. He also has been a member of the HART Board of Directors since February 2013. “Jim is the ideal person to lead HART at this time,” said John F. Kennedy, Chairman of the Board of Directors at HART. “Jim brings his extensive experience developing, leading and growing life science businesses to our company. He spent 12 years in senior management roles at Genzyme, and as a key leader of the Bio Surgery business there Jim led the commercial development and launch of innovative tissue engineered products. He also brings extensive experience in the fields of personalized medicine and medical devices. For the past two years, Jim has provided invaluable insights as a member of our board, and we expect that HART will benefit greatly from his dedicated guidance as CEO.” Mr. Kennedy continued, “We also thank Tom McNaughton, our Chief Financial Officer, for the great work he has done as interim CEO. He and Saverio La Francesca, our Chief Medical Officer, have continued to drive forward our programs and collaborations that are crucial to our success.” “I’m eager to work more closely with the entire HART team to make bioengineered organs for the airways and esophagus available to patients,” said Mr. McGorry. “HART has the potential to change the way patients are treated with organ implants that the body integrates as its own. I look forward to working with the team and HART’s collaborators to make these goals a reality.” Mr. McGorry most recently served as Executive Vice President and General Manager, Translational Oncology Solutions for Champions Oncology and previously was Executive Vice President of Commercial Operations at Accellent. During his 12-year tenure at Genzyme, he held leadership positions across several therapeutic areas, including Bio Surgery, Cardiac Surgery, Oncology and Transplant. Mr. McGorry also was President of Clineffect Systems, an electronic medical records company. He began his life sciences career with Baxter Healthcare Corporation, where he spent 11 years in positions of increasing responsibility. Mr. McGorry also served as an officer in the United States Army for six years, including commanding a special operations Green Beret SCUBA detachment. Mr. McGorry has an MBA with a concentration in healthcare from Duke University, Fuqua School of Business, and a B.S. in engineering from the United States Military Academy at West Point where he was the president of his class. HART plans to provide a corporate update on its second quarter financial call in August following a business review by Mr. McGorry and the management team. About Harvard Apparatus Regenerative Technology Harvard Apparatus Regenerative Technology (HART) is a biotechnology company developing bioengineered organs for clinical use. Our first product, the HART-Trachea, is intended to replace or repair a trachea that has been severely damaged by either physical trauma or trachea cancer. The HART-Trachea technology has been used in several human trachea transplants to date approved under compassionate use exemptions, but none of the Company’s products are yet approved by a government regulatory authority for marketing. The trademark “Harvard Apparatus” is used under a sublicense agreement with Harvard Bioscience, which has licensed the right to use such trademark from Harvard University. Forward-Looking Statements Some of the statements in this press release are "forward-looking" and are made pursuant to the safe harbor provision of the Private Securities Litigation Reform Act of 1995. These "forward-looking" statements in this press release include, but are not limited to, statements relating to the availability and approval of the HART-Trachea or any other HART product candidates, such as the esophagus and bronchus, for patients and related surgeries; regulatory approval of the HART-Trachea or any other HART product candidates, including the esophagus and bronchus, by the FDA, EMA, MHRA or otherwise, which such approvals may not be obtained on a timely basis or at all; success with respect to any clinical trials and other regulatory approval efforts, commercialization efforts and marketing approvals of HART’s product candidates, including our HART-Trachea product, and the continued availability of a market for the HART securities. These statements involve risks and uncertainties that may cause results to differ materially from the statements set forth in this press release, including, among other things, our ability to obtain and maintain regulatory approval for the biologic products, scaffolds, bioreactors and other devices and product candidates we pursue; the success of our clinical trials and products; our inability to operate effectively as a stand-alone, publicly traded company; plus other factors described under the heading “Item 1A. Risk Factors” in our Annual Report on Form 10-K for the fiscal year ended December 31, 2014 or described in our other public filings. Our results may also be affected by factors of which we are not currently aware. The forward-looking statements in this press release speak only as of the date of this press release. Harvard Apparatus Regenerative Technology expressly disclaims any obligation or undertaking to release publicly any updates or revisions to such statements to reflect any change in its expectations with regard thereto or any changes in the events, conditions or circumstances on which any such statement is based.

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