mTOR x MEK

IRVINE, Calif., May 23, 2024 /PRNewswire/ -- Postsurgical Therapeutics, Inc. (PST) today announced the successful completion of an in vivo study of its proprietary injectable gel formulation containing two drugs used to treat several types of KRAS mutated solid tumors. The results demonstrated suppression or elimination of tumors in mice. The drugs were developed and commercialized by others for oral administration. PST's proprietary controlled release gel formulation of the drugs was administered by intratumoral injection to the target tumors. The drugs used target the MAPK and PI3K pathways using a combination of MEK and mTOR inhibitors, which are important for treatment of several major tumor types. The formulation was shown to be effective, reducing growth or eradicating tumors in several KRAS mutations across multiple cancer cell lines, including pancreatic (Mia PaCa-2, G12C), lung (NCI H441, G12V), colorectal (SW3, G12V), and gastric (AGS, G12D) cancers. In clinical practice, multiple drugs are often required as resistance to a single drug limits its therapeutic use. However, clinic investigations by others of combinations of these two drugs by oral administration have not been able to determine a safe and effective dose due to cumulative toxicity as reported by Tolcher (Tolcher et al. Annals of Oncology, 58-64 (2015)) and by Nikanjam (Nikanjam et al. J. Hematol. Oncol. Pharm, 19-25 (2023)). Soonkap Hahn, Ph.D., Chairman, Chief Scientific Officer, and Founder of PST stated that "If clinical trials confirm the results of this study, we believe the resulting product will have the potential to extend the lives of treated patients. We will also investigate the potential reduction in toxicity by local administration." PST is a development stage company based in Irvine, California. PST uses advanced drug delivery technologies to formulate products with enhanced efficacy and safety for the treatment of solid tumors and other therapy areas. PST intends to develop and commercialize products based on its technology through collaborations with corporate partners and others. SOURCE Postsurgical Therapeutics

Researchers have developed a new AI tool to that generate new drug candidates for cancer, which could help streamline the typically laborious drug discovery process. Scientists at UC San Diego have developed a machine learning algorithm to simulate the time-consuming chemistry involved in the earliest phases of drug discovery, which could significantly streamline the process and open doors for never-before-seen treatments. Identifying candidate drugs for further optimization typically involves thousands of individual experiments, but the new artificial intelligence (AI) platform could potentially give the same results in a fraction of the time. The researchers used the new tool, described in Nature Communications, to synthesize 32 new drug candidates for cancer. The technology is part of a new but growing trend in pharmaceutical science of using AI to improve drug discovery and development. "A few years ago, AI was a dirty word in the pharmaceutical industry, but now the trend is definitely the opposite, with biotech startups finding it difficult to raise funds without addressing AI in their business plan," said senior author Trey Ideker, professor in the Department of Medicine at UC San Diego School of Medicine and adjunct professor of bioengineering and computer science at the UC San Diego Jacobs School of Engineering. "AI-guided drug discovery has become a very active area in industry, but unlike the methods being developed in companies, we're making our technology open source and accessible to anybody who wants to use it." The new platform, called POLYGON, is unique among AI tools for drug discovery in that it can identify molecules with multiple targets, while existing drug discovery protocols currently prioritize single target therapies. Multi-target drugs are of major interest to doctors and scientists because of their potential to deliver the same benefits as combination therapy, in which several different drugs are used together to treat cancer, but with fewer side effects. "It takes many years and millions of dollars to find and develop a new drug, especially if we're talking about one with multiple targets." said Ideker. "The rare few multi-target drugs we do have were discovered largely by chance, but this new technology could help take chance out of the equation and kickstart a new generation of precision medicine." The researchers trained POLYGON on a database of over a million known bioactive molecules containing detailed information about their chemical properties and known interactions with protein targets. By learning from patterns found in the database, POLYGON is able to generate original chemical formulas for new candidate drugs that are likely to have certain properties, such as the ability to inhibit specific proteins. "Just like AI is now very good at generating original drawings and pictures, such as creating pictures of human faces based off desired properties like age or sex, POLYGON is able to generate original molecular compounds based off of desired chemical properties," said Ideker. "In this case, instead of telling the AI how old we want our face to look, we're telling it how we want our future drug to interact with disease proteins." To put POLYGON to the test, the researchers used it to generate hundreds of candidate drugs that target various pairs of cancer-related proteins. Of these, the researchers synthesized 32 molecules that had the strongest predicted interactions with the MEK1 and mTOR proteins, a pair of cellular signaling proteins that are a promising target for cancer combination therapy. These two proteins are what scientists call synthetically lethal, which means that inhibiting both together is enough to kill cancer cells even if inhibiting one alone is not. The researchers found that the drugs they synthesized had significant activity against MEK1 and mTOR, but had few off-target reactions with other proteins. This suggests that one or more of the drugs identified by POLYGON could be able to target both proteins as a cancer treatment, providing a list of choices for fine-tuning by human chemists. "Once you have the candidate drugs, you still need to do all the other chemistry it takes to refine those options into a single, effective treatment," said Ideker. "We can't and shouldn't try to eliminate human expertise from the drug discovery pipeline, but what we can do is shorten a few steps of the process." Despite this caution, the researchers are optimistic that the possibilities of AI for drug discovery are only just being explored. "Seeing how this concept plays out over the next decade, both in academia and in the private sector, is going to be very exciting." said Ideker. "The possibilities are virtually endless." This study was funded, in part, by the National Institutes of Health (Grants CA274502, GM103504, ES014811, CA243885, CA212456).

SYDNEY, Nov. 10, 2023 /PRNewswire/ -- Kazia Therapeutics Limited (NASDAQ: KZIA; ASX: KZA), an oncology-focused drug development company, is pleased to announce the publication in Molecular Cancer Therapeutics highlighting paxalisib preclinical data stemming from the research collaboration with the Huntsman Cancer Institute at the University of Utah in Salt Lake City, UT. The paper by Dr Gennie Parkman and colleagues, working in the laboratory of Professor Sheri Holmen, has shown paxalisib to be active in vitro and in vivo against preclinical models of metastatic melanoma, the most aggressive form of skin cancer. Dr Parkman's data highlights paxalisib as a dual inhibitor of both the PI3K and MTOR pathways and cites in the manuscript that paxalisib, "may represent a promising therapeutic strategy in this disease in both the first line and MAPK inhibitor resistant setting" for BRAF-mutant cutaneous melanoma. "This is promising data for paxalisib, which reinforces its potential for use in an area outside of our traditional brain cancer areas of focus," commented Dr John Friend, Kazia's CEO. "We are privileged to be working with one of the world's leading melanoma centers on this outstanding research project and hope it may lead to a new way of treating melanoma for patients without suitable therapies." Key Points from the Publication Activation of the PI3K / Akt / mTOR pathway, which is the target of paxalisib, is common in melanoma and has been identified as a key resistance mechanism to some established therapies. In vitro: Treatment with paxalisib was observed to lead to a significant decrease in melanoma cell growth in multiple cell lines and was also observed to inhibit downstream signaling through the PI3K/AKT cascade, leading to its negative effect on melanoma cell growth. In vivo: Mice bearing tumors who were dosed with 15 mg/kg paxalisib daily; paxalisib was observed to inhibit of tumor growth and significantly extended the overall survival of these mice (p=0.0003) compared to vehicle In a MTG004 patient derived xenograft mouse model that is resistant to dabrafenib and trametinib (inhibitors of mutant BRAF and MEK, respectively). At day 21, the mean tumor volume in the paxalisib treated mice was observed to be significantly lower than vehicle (P = .05) or dabrafenib/trametinib treated mice (P = .01) The authors concluded: "Our results support the use of paxalisib as a single agent either in the first line or MAPK inhibitor resistant setting for BRAF-mutant cutaneous melanoma. In this paper, we demonstrate the beneficial use of next generation PI3K/mTOR inhibitors, notably paxalisib, to inhibit melanoma cell growth." The paper has been published online in Molecular Cancer Therapeutics and can be accessed at the following website: Melanoma Approximately 1 in 50 people will be diagnosed with melanoma during their lifetime. Most cases are localized to the skin and can be cured through surgical resection. However, about 20% of cases spread (metastasis) and require more complex and ongoing treatment. Melanoma represents approximately 1% of all skin cancers, but accounts for the majority of deaths from skin cancer. For melanoma that is confined to the skin at the time of diagnosis, the five-year survival rate is 99.5%. However, for melanoma that has spread to distant sites (metastatic melanoma), the five-year survival rate falls to 32%. Approximately 50% of patients harbor activating mutations in the BRAF gene. Such patients are typically treated with the combination of a BRAF inhibitor and a MEK inhibitor. The introduction of targeted therapies has improved the average survival of patients with BRAF-mutant metastatic melanoma from approximately 6 months to approximately 24 months. However, we believe there remains a need for additional therapeutic options to further improve survival. Next Steps Kazia anticipates further data from the ongoing collaboration with the Huntsman Cancer Institute in CY2024. Depending on the results, Kazia may evaluate future opportunities to launch a clinical trial of paxalisib in melanoma. This announcement was authorized for release by Dr. John Friend, CEO. About Kazia Therapeutics Limited Kazia Therapeutics Limited (NASDAQ: KZIA; ASX: KZA) is an oncology-focused drug development company, based in Sydney, Australia. Our lead program is paxalisib, a brain-penetrant inhibitor of the PI3K / Akt / mTOR pathway, which is being developed to treat multiple forms of brain cancer. Licensed from Genentech in late 2016, paxalisib is or has been the subject of ten clinical trials in this disease. A completed Phase 2 study in glioblastoma reported promising signals of clinical activity in 2021, and a pivotal study, GBM AGILE, is ongoing, with final data expected in CY2023. Other clinical trials are ongoing in brain metastases, diffuse midline gliomas, and primary CNS lymphoma, with several of these having reported encouraging interim data. Paxalisib was granted Orphan Drug Designation for glioblastoma by the US Food and Drug Administration (US FDA) in February 2018, and Fast Track Designation for glioblastoma by the US FDA in August 2020. In addition, paxalisib was granted Rare Pediatric Disease Designation and Orphan Designation by the US FDA for DIPG in August 2020, and for atypical teratoid / rhabdoid tumours (AT/RT) in June 2022 and July 2022, respectively. Kazia is also developing EVT801, a small-molecule inhibitor of VEGFR3, which was licensed from Evotec SE in April 2021. Preclinical data has shown EVT801 to be active against a broad range of tumour types and has provided evidence of synergy with immuno-oncology agents. A Phase 1 study in advanced solid tumors commenced recruitment in November 2021. For more information, please visit or follow us on Twitter @KaziaTx. Forward-Looking Statements This announcement may contain forward-looking statements, which can generally be identified as such by the use of words such as "may," "will," "estimate," "future," "forward," "anticipate," or other similar words. Any statement describing Kazia's future plans, strategies, intentions, expectations, objectives, goals or prospects, and other statements that are not historical facts, are also forward-looking statements, including, but not limited to, statements regarding: the timing for results and data related to Kazia's clinical and preclinical trials, and Kazia's strategy and plans with respect to its programs, including paxalisib and EVT801, as well as any potential future indications for such programs. Such statements are based on Kazia's current expectations and projections about future events and future trends affecting its business and are subject to certain risks and uncertainties that could cause actual results to differ materially from those anticipated in the forward-looking statements, including risks and uncertainties: associated with clinical and preclinical trials and product development, related to regulatory approvals, and related to the impact of global economic conditions. These and other risks and uncertainties are described more fully in Kazia's Annual Report, filed on form 20-F with the SEC, and in subsequent filings with the United States Securities and Exchange Commission. Kazia undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise, except as required under applicable law. You should not place undue reliance on these forward-looking statements, which apply only as of the date of this announcement. SOURCE Kazia Therapeutics Limited