An international team led by scientists at the National Institutes of Health is the first to discover a new way that cells fix an important and dangerous type of DNA damage known as a DNA-protein crosslink (DPC) (Article, US NIH, OCT 6, 2017, View Source [SID1234520808]). The researchers found that a protein named ZATT can eliminate DPCs with the help of another protein, TDP2. Since DPCs form when individuals receive some types of cancer treatments, understanding how TDP2 and ZATT work together to repair the damage may improve the health outcomes of cancer patients. The findings were published in the journal Science.

Researchers knew that TDP2 was important for removing DPCs, but they did not know how it was directed to where it needed to work, according to corresponding author Scott Williams, Ph.D., deputy chief of the Genome Integrity and Structural Biology Laboratory at the National Institute of Environmental Health Sciences (NIEHS), part of NIH. Williams and his team used a multi-pronged approach to identify ZATT as a new contributor to this process and determine how it guides TDP2 to DPCs so they can be repaired.

To visualize how these proteins choreograph DPC repair, one must first know how DPCs are created. Matthew Schellenberg, Ph.D., an NIEHS visiting fellow and lead author on the paper, said when DNA becomes tangled inside of cells, organisms use a protein called topoisomerase 2 (TOP2) to untangle it.

“Imagine your DNA is a giant ball of yarn,” Schellenberg said. “TOP2 cuts and reties individual threads to disentangle the ball.”

Schellenberg explained that TOP2 normally conceals its cut DNA ends within the core of the TOP2 protein that encircles DNA. Doing so ensures the protein can complete the second part of its job, which is rejoining DNA ends. However, chemotherapeutic drugs or environmental chemicals sometimes block the protein’s DNA-retying ability, so that TOP2 remains stuck on DNA. This situation creates a stable TOP2-DPC complex, which leads to the accumulation of severed DNA that kills cells.

Williams likened TOP2-DPCs to ticking time bombs for cells. He said these molecular charges are armed by TOP2’s interaction with environmental toxicants, chemical metabolites, tobacco exposures, or DNA damage caused by ultraviolet light.

He added that TOP2-DPCs are most potently formed by pharmaceutical drugs that humans exploit to eradicate cancer cells, making TOP2-DPCs double-edged swords. If they are not removed, they trigger cell death. While cancer drugs induce formation of TOP2-DPCs to treat cancer, TOP2-DPC lesions can also be the source of disease, as they can cause rearrangement of an organism’s genome that leads to cancer. For this reason, Williams and his colleagues said it was necessary to learn how DPCs are located and broken down.

“In this study, we discovered a new molecular disarmament apparatus for these cell-killing bombs,” Williams said. “ZATT is like a bomb sniffing dog, so when it locates its target, it sounds an alarm to mobilize the recruitment of TDP2, which cuts the red wire to disarm these threats.”

Schellenberg said chemotherapeutic drugs, such as etoposide, are not the only pharmaceuticals that induce DPCs. Many of the antibiotics that are currently on the market use the same method to damage bacterial DNA. He said this work was part of a larger effort to figure out how researchers can exploit this key vulnerability to improve health.

“We’ve discovered how we defend against this potent means of cell killing,” Schellenberg said. “It is our hope that this information will enable development of new drugs that target these defenses. By lowering the defenses, we may make drugs that kill cancer cells more effective.”

Grant Numbers: ZIAES102765, ZICES102488, ZIAES050111, R01GM105404

NIEHS supports research to understand the effects of the environment on human health and is part of NIH. For more information on environmental health topics, visit www.niehs.nih.gov. Subscribe to one or more of the NIEHS news lists to stay current on NIEHS news, press releases, grant opportunities, training, events, and publications.

On October 6, 2017 Eli Lilly and Company (NYSE: LLY) reported that interim results from the double-blind, placebo-controlled Phase 3 MONARCH 3 study evaluating VerzenioTM (abemaciclib), a cyclin-dependent kinase (CDK)4 & 6 inhibitor, in combination with a nonsteroidal aromatase inhibitor (NSAI) (anastrozole or letrozole) were published online in the Journal of Clinical Oncology (JCO) (Press release, Eli Lilly, OCT 6, 2017, View Source [SID1234520807]). These data, presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress in September, demonstrated that abemaciclib plus an NSAI resulted in a statistically significant improvement in progression-free survival (PFS) and objective response rate (ORR) compared to an NSAI alone in women with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer.

“The significant results seen in MONARCH 3 confirm the clinical value of combining abemaciclib with an aromatase inhibitor in patients with endocrine-sensitive advanced breast cancer, and we look forward to seeing the final PFS data in the coming months,” said lead author Matthew P. Goetz, M.D., professor of oncology and pharmacology at Mayo Clinic and co-lead investigator of the MONARCH 3 study. “These data further demonstrate that abemaciclib is an effective treatment in the CDK4 & 6 class. This class represents a new standard of care in the treatment of advanced breast cancer.”

MONARCH 3 met a rigorous threshold for demonstrating efficacy at the time of pre-planned interim analysis with a 46 percent reduction in the risk of progression or death in patients receiving initial therapy for metastatic disease. The median PFS for abemaciclib in combination with an NSAI was not reached (i.e., the disease had not progressed significantly), compared to 14.7 months in the placebo arm (HR: 0.54; 95% CI: 0.41-0.72; P=0.000021). These results are supported by an improvement in response rate, with a 59.2 percent ORR in patients with measurable disease, including five patients (1.5%) achieving a complete response. Median duration of response (DoR) was not reached in the abemaciclib-plus-NSAI arm. Final PFS results are expected at the end of the year and will be presented at a scientific congress in the first half of 2018.

“At Lilly, we remain deeply committed to delivering standard-of-care changing medicines that improve the lives of many cancer patients,” said Levi Garraway, M.D., Ph.D., senior vice president, global development and medical affairs, Lilly Oncology. “We now have evidence from two randomized trials showing that the addition of Verzenio to an endocrine therapy provides clinical benefit to women with metastatic breast cancer and we look forward to further advancing our MONARCH clinical program.”

In MONARCH 3, abemaciclib in combination with an NSAI was generally well tolerated. The most frequent adverse events (AEs) of any grade in the abemaciclib-plus-NSAI arm were diarrhea, neutropenia, fatigue, infections, and nausea. Of these, the reported Grade 3/4 AEs in the abemaciclib-plus-NSAI arm versus the placebo-plus-NSAI arm were diarrhea (Grade 3: 9.5% vs 1.2%; no Grade 4 observed), neutropenia (Grade 3: 19.6% vs 0.6%; Grade 4: 1.5% vs 0.6%), fatigue (Grade 3: 1.8% vs 0%; no Grade 4 observed), infections (Grade 3: 4.0% vs 2.5%; Grade 4: 0.9% vs 0.6%), and nausea (Grade 3: 0.9% vs 1.2%; no Grade 4 observed).

Severity and frequency of diarrhea generally decreased following 28 days (one month), and was managed with over-the-counter antidiarrheal medication and dose adjustment. The majority (76.3%) of patients in the abemaciclib-plus-NSAI arm with an AE of diarrhea did not require treatment modification (dose interruption, reduction, or discontinuation), and 2.3 percent of patients discontinued treatment with abemaciclib due to diarrhea.

The MONARCH 3 study also included exploratory subgroup analyses that underscored consistency of results (when compared to the overall intention-to-treat [ITT] results) in patients with certain challenging disease characteristics. Further studies are needed to explore these findings.

MONARCH 3 was designed to evaluate the efficacy and safety of abemaciclib in combination with NSAIs as initial endocrine-based therapy for postmenopausal women with advanced (locoregionally recurrent or metastatic) breast cancer who have had no prior systemic treatment for advanced disease. If neoadjuvant/adjuvant endocrine therapy was administered, a disease-free interval of more than 12 months since completion of endocrine therapy was required. A total of 493 patients were randomized 2:1 to receive 150 mg of abemaciclib or placebo orally twice a day, without interruption, given in combination with either 1 mg of anastrozole or 2.5 mg of letrozole once daily until disease progression or unacceptable toxicity. The primary endpoint of the study was PFS, with key secondary endpoints of ORR, DoR, overall survival and safety.

On October 06, 2017 Molecular Templates, Inc., (Nasdaq:MTEM) a clinical stage biopharmaceutical company focused on the discovery and development of Engineered Toxin Bodies (ETBs), a new class of targeted biologic therapies that possess unique mechanisms of action in oncology, reported that Eric E. Poma, Ph.D., Chief Executive and Chief Scientific Officer, will provide a corporate overview at the 2017 BIO Investor Forum, being held October 17-18 in San Francisco, California (Press release, Molecular Templates, OCT 6, 2017, View Source [SID1234520805]).
BIO Investor Forum
Date: Tuesday, October 17
Time: 10:30am Pacific Time
Location: Westin St. Francis, San Francisco, Elizabethan C Ballroom
Webcast: http://www.veracast.com/webcasts/bio/investorforum2017/25111335172.cfm

On October 6, 2017 Kitov Pharmaceuticals Holdings Ltd. (NASDAQ: KTOV, TASE: KTOV), (“Kitov” or “the Company”) an innovative biopharmaceutical company, reported the acquisition of an additional 27% stake in TyrNovo Ltd., a privately- held developer of novel small molecules in the oncology therapeutic field, from unaffiliated minority shareholders (Press release, Kitov Pharmaceuticals , OCT 6, 2017, View Source [SID1234520804]). As announced on January 13, 2017, Kitov had acquired a controlling interest, which is now approximately 65% of TyrNovo. After the closing of this transaction, Kitov will hold approximately 92% of TyrNovo’s issued and outstanding ordinary shares.

Following negotiations with a group of unaffiliated minority shareholders who collectively hold approximately 27%, of TyrNovo, the Company has entered into an agreement to acquire their shares based on an agreed upon TyrNovo valuation of $7 million. In exchange for these TyrNovo shares, Kitov will issue 13,169,689 new shares (equivalent to 658,484 American Depositary Shares or ADSs) of Kitov, at an agreed upon price, in excess of prevailing market prices, of $2.50 per ADS.

“Since early 2017, NT219 demonstrated impressive efficacy results including in combination with Keytruda, where it converted non-responding tumors to responders and blocked tumor progression in an immuno-oncology preclinical model. We are pleased to have negotiated the opportunity for Kitov to increase its stake in TyrNovo. We are committed to the development of NT219, which we believe is a highly attractive asset for Kitov’s shareholders in the growing field of oncology” stated Mr. Isaac Israel, Chief Executive Officer. “We believe that expanding our ownership in TyrNovo provides a significant opportunity for further growth of Kitov and added value to our shareholders.”

“Based on the pre-clinical results generated to date, we are receiving solid preliminary interest from potential strategic partners for NT219, which presents a novel, first-in-class mechanism of action in the oncology field.”

About NT219

NT219 is a small molecule that presents a new concept in cancer therapy by promoting the degradation and the phosphorylation of two oncology-related checkpoints, Insulin Receptor Substrates (IRS) 1 and signal transducer and activator of transcription 3 (STAT3), respectively. While targeted anti-cancer drugs inhibit the “ON” signal, NT219 activates the “OFF” switch, extensively blocking major oncogenic pathways. In pre-clinical trials, NT219, in combination with several approved cancer drugs, displayed potent anti-tumor effects and increased survival in various cancers by preventing the tumors from developing -drug resistance and reversing resistance after it has been acquired. In combination with various approved oncology drugs, NT219 demonstrated potent anti-tumor effects and increased survival in various cancer models including sarcoma, melanoma, pancreatic, lung, ovarian, head & neck, prostate and colon cancers, through the prevention of acquired resistance and regression of resistant tumors.