HSF1

Prostate cancer that has become resistant to hormone therapy could be treated using a new drug that is currently in clinical trials for ovarian and bile duct cancer, according to research published in the journal Clinical Cancer Research. Scientists from The Institute of Cancer Research, London, showed that the drug, NXP800, discovered at the same institute, slowed the growth of prostate cancer cells, including in cancer cells that are resistant to the hormone therapy enzalutamide. Although hormone therapies like enzalutamide and abiraterone transform the lives of thousands of men with advanced prostate cancer every year, most patients will eventually become resistant to these treatments. Researchers are searching for new ways to overcome drug resistance. NXP800 works in an innovative way, by targeting the Heat Shock Factor 1 (HSF1) pathway – a ‘master switch’ in cells that is hijacked to support the growth of cancer cells, helping them withstand the stresses they come under as a tumour develops. The pathway controls the production of heat shock proteins that help to protect the cancer cell during stressful conditions. The team at The Institute of Cancer Research (ICR) studied data from 439 advanced prostate cancer samples. In research funded largely by Prostate Cancer UK, Movember, and the Prostate Cancer Foundation, they found an association between higher levels of heat shock proteins and more androgen receptor signalling, which drives the development and growth of prostate cancer. They also found an association between patients who had higher levels of these proteins and poorer overall survival. In one cohort they studied, patients with more of these proteins survived for 22.0 months, compared with 33.5 months for those with fewer heat shock proteins, suggesting that prostate cancers with more of these proteins may be better equipped to survive and harder to treat. The researchers attempted to block these heat shock proteins using the drug NXP800, which was discovered at the ICR in its Centre for Cancer Drug Discovery. The drug underwent an early clinical trial in advanced cancer, led by the ICR and its hospital partner The Royal Marsden NHS Foundation Trust, and sponsored by Nuvectis Pharma. In the lab, the researchers found that NXP800 slowed the growth of prostate cancer cells – even for cells which were resistant to the hormone therapy enzalutamide. In biopsies of patients with advanced prostate cancer grown as mini tumours in the laboratory, the new drug slowed the growth of the tumours, whereas enzalutamide only had a small effect at very high concentrations. In mice with hormone therapy-resistant prostate cancers, NXP800 significantly slowed tumour growth. Without the drug, 100 per cent of tumours had doubled in size by 38 days – when treated with the drug, only 37.5 per cent of tumours had reached that size in that time. The researchers from the ICR, which is both a research institute and a charity, hope these findings will lead to trials of NXP800 for advanced prostate cancer, to provide patients with alternative treatments when hormone therapies have stopped working. The team carried out mechanistic studies which confirmed that NXP800 blocks the activity of HSF1 in prostate cancer cells and reduces the levels of heat shock proteins. They also discovered that it modulates a pathway called the unfolded protein response – a pathway connected to the cells’ response to stress – and impacts other protein molecules that are important in controlling gene activity in prostate cancer. Understanding the mechanism of the drug’s action will be important for future research to discover which patients will respond best. NXP800 has been granted Fast-Track and Orphan Drug Designation by the US Food and Drug Administration (FDA) for its potential to treat ARID1a-deficient ovarian, fallopian tube, and peritoneal cancers, and Orphan Drug Designation for hard-to-treat bile duct cancer. This is to speed up the review of, and provide financial benefits for, drugs which show promise to treat rare diseases. Until this study, it had not been considered for use in prostate cancer. Study co-leader Dr Adam Sharp, Leader of the Translational Therapeutics Group at The Institute of Cancer Research, London, and Honorary Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust said: “While hormone therapies have extended the lives of lots of men with advanced prostate cancer, drug resistance is inevitable. We need to tackle the problem from a new angle. “With this research, we’ve shown that targeting the heat shock response pathway – a pathway responsible for enabling tumours to withstand stress and keep growing – is a potential new avenue for treating advanced prostate cancer. The pathway impacts the hormone signalling that drives cancer, but it’s not susceptible to the usual mutations that drive drug resistance. “Excitingly, we’ve shown that targeting this pathway can slow the growth of prostate cancer tumours – even for tumours that are resistant to hormone therapy. The next step will be to assess if certain prostate cancer patients would respond better than others. “The researchers Jon Welti, Denisa Bogdan and Ines Figueredo, played a critical role in this research to establish the effect of NXP800 on prostate cancer.” Study co-leader Professor Johann de Bono, Regius Professor of Cancer Research at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust said: “We have shown that people with prostate cancers with higher levels of heat shock proteins have significantly worse outcomes. If targeting these proteins proves effective in clinical trials, patients with advanced prostate cancer will be able to look forward to longer and better-quality lives.” Professor Kristian Helin, Chief Executive at The Institute of Cancer Research, London, said: “Drug resistance is one of the biggest problems we face in treating cancer. Finding drugs that can slow down cancer’s growth when all other treatments have stopped working is critical. “This research uses an innovative drug to target prostate cancer through a novel mechanism of action. We’ve been delighted to see the ICR-discovered NXP800 drug make great progress in clinical studies for ovarian cancer, so it is very exciting to see that it could potentially also benefit prostate cancer patients for whom hormone therapy has stopped working. “NXP800 is one of the 13 ICR-discovered drugs we’ve taken into clinical trials for cancer patients since 2005. That track record is unrivalled in the academic world.” Professor Paul Workman, Harrap Professor of Pharmacology and Therapeutics at The Institute of Cancer Research, London, who led the original research at the ICR to discover NXP800 and is a co-author of this study, said: “The NXP800 drug is an example of the incredible drug discovery and development that is possible through partnerships between academics, clinicians and private enterprise. Through our Centre for Cancer Drug Discovery and our close partnership with The Royal Marsden, the ICR has unparalleled capabilities for discovering and developing totally new types of treatment for patients with hard-to treat cancers. “I’m thrilled about the exciting results we’ve obtained in prostate cancer models, which means that the drug could benefit even more patients beyond the current focus on ovarian and bile duct cancer. “NXP800 works through a highly innovative mechanism and I very much hope to eventually see the drug, now licenced to the US biotechnology Nuvectis Pharma, progress into additional trials including for advanced prostate cancer.” Simon Grieveson, Assistant Director of Research at Prostate Cancer UK, said: "For men with advanced prostate cancer, treatment with hormone therapy can be very effective at delaying cancer progression, however eventually these treatments are likely to stop working. This is a critical problem we need to address through continued research into brand new approaches to treating prostate cancer, and this is a fantastic example. “We’re thrilled to have funded this research in partnership with Movember, which could make a marked impact on the lives of men with hormone resistant prostate cancer and who have very few treatment options remaining. These findings provide valuable insight into the role of heat shock proteins, which we now know are at a higher level among advanced prostate cancer patients and associated with worse outcomes. Targeting these proteins with this novel drug could give men with hormone resistant prostate cancer a new option for treatment and, crucially, more valuable time with their loved ones. Clinical trials are now needed, but this is an exciting step towards a new solution to tackling treatment resistance in prostate cancer." Howard R. Soule, PhD, Executive Vice President and Chief Science Officer of the Prostate Cancer Foundation, said: “These findings fill a therapeutic gap for patients with advanced prostate cancer. We applaud the discovery and clinical translational expertise of the ICR in advancing a new target and novel experimental therapy to the patients PCF serves.”

NXP800 demonstrated robust antitumor activity in two patient-derived xenograft (“PDX”) models of cholangiocarcinomaResearch conducted by investigators from the Mayo Clinic in Rochester, MN Fort Lee, NJ, April 18, 2023 (GLOBE NEWSWIRE) -- Nuvectis Pharma, Inc. (NASDAQ: NVCT) ("Nuvectis" or the "Company"), a clinical-stage biopharmaceutical company focused on the development of innovative precision medicines for the treatment of serious conditions of unmet medical need in oncology, today provided highlights from the poster presentation of NXP800 that took place yesterday at the American Association for Cancer Research (“AACR”) Annual Meeting 2023 in Orlando, FL (to view the poster, titled Inhibition of HSF1 Demonstrates Therapeutic Efficacy in Preclinical PDX Models of Human Cholangiocarcinoma, click here). Ron Bentsur, Chairman and Chief Executive Officer of Nuvectis, commented, “Cancer of the bile duct, or cholangiocarcinoma (“CCA”), is a serious unmet medical need for which new treatment options are greatly needed. With approximately 10,000 new cases per year in the United States, the clinical management of CCA is complex, with only about 30% of patients eligible for surgical resection and the rest with unresectable disease, which carries a dismal prognosis with a median survival of less than 1 year. Unfortunately, approximately 60% of the patients that do undergo surgical resection experience disease recurrence and face similar outcomes.” Mr. Bentsur concluded, “We are excited about the data generated as we continue to evaluate clinical development opportunities for NXP800.” Dr. Rory L. Smoot, MD, Mayo Clinic, who led the research, added: "We are encouraged by the robust preclinical activity demonstrated by NXP8000 in these CCA PDX models, which we believe serve as good indicators for potential clinical benefit. CCA is a very difficult to treat disease with poor outcomes and today's results provide promise for patients in the future." About Nuvectis Pharma, Inc. Nuvectis Pharma, Inc. is a biopharmaceutical company focused on the development of innovative precision medicines for the treatment of serious conditions of unmet medical need in oncology. The Company is currently developing two drug candidates, NXP800 and NXP900. NXP800 is a clinical-stage, oral small molecule under development for the treatment of platinum-resistant, ARID1a-mutated ovarian carcinoma and additional solid tumor types. The FDA granted Fast Track Designation to NXP800 for the treatment of platinum-resistant, ARID1a-mutated ovarian carcinoma. NXP900 is a novel, small molecule SRC/YES1 kinase inhibitor with an Investigational New Drug (“IND”) application pending. Forward Looking Statements This press release contains "forward-looking statements" within the meaning of the federal securities laws, which statements are subject to substantial risks and uncertainties. All statements, other than statements of historical fact, contained in this press release are forward-looking statements. Forward-looking statements contained in this press release may be identified by the use of words such as "anticipate," "believe," "contemplate," "could," "estimate," "expect," "intend," "seek," "may," "might," "plan," "potential," "predict," "project," "target," "aim," "should," "will," "would," or the negative of these words or other similar expressions, although not all forward-looking statements contain these words. Forward-looking statements are based on Nuvectis Pharma, Inc.'s current expectations, estimates, and projections about future events and trends that we believe may affect our business, financial condition, results of operations, prospects, business strategy, and financial needs. The outcome of the events described in these forward-looking statements are subject to inherent uncertainties, risks, assumptions, market and other conditions, and other factors that are difficult to predict and include statements regarding the preclinical data generated to date for NXP800, including the preclinical data in cholangiocarcinoma, and for NXP900, the Phase 1a data generated and the Phase 1b clinical expectations for NXP800, including the safety, tolerability and other observations from the NXP800 Phase 1a study and timing, and safety, tolerability and efficacy data from the NXP800 Phase 1b study, including statements regarding NXP800's potential ability to become a therapeutic option for the treatment of platinum-resistant, ARID1a-mutated ovarian carcinoma, ARID1a-mutated or wildtype cholangiocarcinoma, and potentially other cancer indications, and timing for the IND acceptance and commencement of the Phase 1 program for NXP900. Further, certain forward-looking statements are based on assumptions as to future events that may not prove to be accurate. These and other risks and uncertainties are subject to market and other conditions and described more fully in the section titled "Risk Factors" in our 2022 Form 10-K filed with the Securities and Exchange Commission ("SEC"). However, these risks are not exhaustive and new risks and uncertainties emerge from time to time, and it is not possible for us to predict all risks and uncertainties that could have an impact on the forward-looking statements contained in this press release or other filings with the SEC. Any forward-looking statements contained in this press release speak only as of the date of this press release. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions or circumstances on which any such statement is based, except as may be required by law, and we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995. Company ContactRon BentsurChairman, Chief Executive Officer and PresidentTel: 201-614-3151rbentsur@nuvectis.com Media Relations ContactChristopher M. CalabreseLifeSci AdvisorsTel: 917-680-5608ccalabrese@lifesciadvisors.com

Phase 1b study builds on highly consistent preclinical and Phase 1a data Fort Lee, NJ, USA I April 10, 2023 I Nuvectis Pharma, Inc. (NASDAQ: NVCT) ("Nuvectis" or the "Company"), a clinical-stage biopharmaceutical company focused on the development of innovative precision medicines for the treatment of serious conditions of unmet medical need in oncology, today announced the initiation of the Phase 1b study for NXP800 in platinum-resistant, ARID1a-mutated ovarian carcinoma. The Phase 1b study is a multicenter, single-agent, open-label clinical trial of NXP800 in patients with platinum-resistant, ARID1a-mutated ovarian cancer, a tumor type that is comprised almost exclusively of ovarian clear-cell carcinoma (“OCCC”) and ovarian endometrioid carcinoma (“OEC”). The study will examine the safety, tolerability and preliminary efficacy of NXP800 in this target patient population. The study will enroll two cohorts of up to approximately 25 patients each and will evaluate two dosing regimens, 50 mg and 75 mg, administered once daily, selected based on data from the Phase 1a dose escalation study in patients with various types of advanced solid tumors. The study will be conducted in 25-30 sites in the United States (“U.S.”), United Kingdom (“UK”) and Europe in collaboration with the European Network of Gynaecological Oncological Trial Groups and the GOG Foundation, Inc., recognized as the world's premier gynecology oncology clinical trials consortia. The NXP800 development program in platinum-resistant, ARID1a-mutated ovarian cancer was granted Fast Track Designation by the U.S. Food and Drug Administration (“FDA”). “We are excited to announce the initiation of the Phase 1b study in which NXP800 will be tested, for the first time, in patients with a target disease,” said Ron Bentsur, Chairman and Chief Executive Officer of Nuvectis. “The robust preclinical anti-tumor activity of NXP800, coupled with the data from the Phase 1a dose escalation study, led to the design of the Phase 1b study, including the definition of the patient population and selection of doses and dosing schedules.” Mr. Bentsur concluded, “Based on the totality of the data generated to date, we believe that NXP800 has the potential to become an effective treatment for patients with platinum-resistant, ARID1a-mutated ovarian carcinoma, as well as additional target tumor types, which we plan to also investigate in the near term." About NXP800 NXP800 is an oral, small molecule inhibitor of the HSF1 pathway. NXP800 has demonstrated robust anti-tumor activity in xenograft models of ARID1a-mutated ovarian carcinoma and other disease models. The NXP800 development program in platinum-resistant, ARID1a-mutated ovarian carcinoma was granted Fast Track Designation by the U.S. FDA. Nuvectis licensed exclusive world-wide rights to NXP800 from the Institute of Cancer Research in London, UK. Phase 1a Data Highlights About Platinum-Resistant, ARID1a-Mutated Ovarian Carcinoma ARID1a-mutated ovarian carcinoma is comprised almost exclusively of two histologies, OCCC and OEC, each representing about 10% of the overall ovarian cancer cases in the U.S. with an annual incidence of approximately 2,200 patients per histology. Platinum resistant ovarian carcinoma is recognized as a serious condition of unmet medical need, given the lack of effective treatments and the poor patient prognosis in this setting. It is estimated that approximately 66% of patients with OCCC and 40% of patients with OEC have the ARID1a mutation, supporting the potential opportunity for the use of NXP800 as a new therapeutic option. About Nuvectis Pharma, Inc. Nuvectis Pharma, Inc. is a biopharmaceutical company focused on the development of innovative precision medicines for the treatment of serious conditions of unmet medical need in oncology. The Company is currently developing two drug candidates, NXP800 and NXP900. NXP800 is a clinical-stage, oral small molecule under development for the treatment of platinum-resistant, ARID1a-mutated ovarian carcinoma and additional solid tumor types. The FDA granted Fast Track Designation to NXP800 for the treatment of platinum-resistant, ARID1a-mutated ovarian carcinoma. NXP900 is a novel, small molecule SRC/YES1 kinase inhibitor with an Investigational New Drug (“IND”) application pending. SOURCE: Nuvectis Pharma