mTOR x Akt-1

SYDNEY, Dec. 15, 2022 /PRNewswire/ -- Kazia Therapeutics Limited (NASDAQ: KZIA; ASX: KZA), an oncology-focused drug development company, is pleased to announce a collaboration with QIMR Berghofer Medical Research Institute, one of Australia's foremost cancer research centres, to explore novel uses of paxalisib in solid tumours. The research project is led by Professor Sudha Rao, a leading expert in transcriptional biology, particularly as it applies to the function of the immune system in cancer. Professor Rao's laboratory works closely with pharmaceutical companies and with clinicians to explore innovative approaches to cancer treatment. The collaboration is ongoing and will build on initial research that has already led to the filing of a patent, including the use of paxalisib as an immune modulator in the treatment of diseases such as breast cancer. Key Points Paxalisib is a member of a class of drugs known as PI3K inhibitors. The direct anti-cancer effects of PI3K inhibitors are well demonstrated, and five therapies have been approved by the US FDA to date. Professor Rao's research identifies an entirely separate effect of PI3K inhibition: as a modulator of the immune microenvironment within and around the tumour. Administration of PI3K inhibitors such as paxalisib, at doses and frequencies different to those conventionally used, appears to activate the immune system in the tumour, making it more susceptive to immunotherapy. The research opens up an important opportunity for paxalisib in combination with drugs such as Keytruda® (pembrolizumab, Merck) and Opdivo® (nivolumab, Bristol Myers Squibb) for the treatment of diseases such as breast cancer and lung cancer. If proven effective in clinical trials, such combinations may have the potential to improve outcomes for patients. It is anticipated that the results of the research will be published in 1H CY2023, and discussions are ongoing regarding potential translation to clinical trials in CY2023. "These are very promising data," commented Professor Rao, Principal Investigator on the project. "In treatment-resistant pre-clinical models of breast cancer, paxalisib has shown encouraging results in inhibiting both the primary tumour burden and metastasis by reinvigorating the immune system within the tumour microenvironment. We look forward to continuing our research, and hopefully seeing this work lead to a clinical trial in due course." "Professor Rao's team are working at the leading edge of cancer research, and we are enormously grateful for their work on paxalisib," said Dr James Garner, CEO of Kazia. "An important part of our recent strategy for the drug has been to expand its field of opportunity outside of cancers of the brain. This work, which has primarily focused on breast cancer, but which has applicability to other solid tumours, builds on some promising data we previously shared which demonstrated the potential of paxalisib in melanoma. We look forward to working with the QIMR Berghofer team to take this research to the next stage." For More Information, Please Contact:- Jane Lowe IR Department [email protected] Phone: +61 411 117 774 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 II study in glioblastoma reported promising signals of efficacy in 2021, and a pivotal study for registration, 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 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 compelling evidence of synergy with immuno-oncology agents. A phase I study 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. Such statements are based on Kazia's 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 the 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 SEC. 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

SYDNEY, Dec. 1, 2022 /PRNewswire/ -- Kazia Therapeutics Limited (NASDAQ: KZIA; ASX: KZA), an oncology-focused drug development company, is pleased to announce the publication of positive preclinical data for EVT801, a clinical-stage drug candidate currently in a clinical trial for multiple forms of cancer. The publication, by Michael Paillasse and colleagues, summarizes a large body of preclinical research conducted principally by scientists at Evotec SE and at the University Cancer Institute of Toulouse - Oncopole over a period of several years. It is now published in Cancer Research Communications, a recently-launched journal published by the American Association of Cancer Research (AACR). The data formed the basis of Kazia's in-licensing of EVT801 from Evotec in 2021 and has since supported transition of the compound into an ongoing phase I clinical trial in patients with advanced solid tumors. Key Points EVT801 is a selective inhibitor of vascular endothelial growth factor receptor 3 (VEGFR3). VEGFs and VEGFRs are well-validated cancer drug targets with multiple FDA-approved products directed to them, but a more selective VEGFR3 inhibitor, such as EVT801, may result in better tolerability and less development of resistance to therapy. EVT801 was confirmed in preclinical studies to be a potent and selective inhibitor of VEGFR3, with activity in the low nanomolar range. The drug was shown to inhibit the formation of lymphatic vessels in vitro, confirming its intended primary mode of action. In vivo (animal) experiments showed EVT801 to be more active than both pazopanib (Votrient®, Novartis) and sorafenib (Nexavar®, Bayer) in the tumor models under investigation. EVT801 combined with immune checkpoint inhibitors in mouse models of several tumor types showed strongly synergistic activity, with the combination performing better than either drug alone. Immune checkpoint inhibitors are widely used in many cancers, and the class includes drugs such as pembrolizumab (Keytruda®, Merck), nivolumab (Opdivo®, Bristol Myers Squibb), and ipilimumab (Yervoy®, Bristol Myers Squibb). "These data demonstrate the substantial potential of EVT801 as a cancer therapeutic," stated Dr Michael Paillasse, lead author of the publication. "EVT801 has been shown to act exactly as intended: by impacting the vasculature in and around the tumor. In addition, the evidence of synergy with immunotherapy is persuasive, and we see a considerable opportunity to combine the drug with immune checkpoint inhibitors in clinical trials." "We are grateful that the results of this public-private translational research initiative have been appreciated by the editors and reviewers of Cancer Research Communications. We will now focus on the clinical development," said Professor Jean-Pierre Delord, co-author and CEO of the IUCT – Oncopole. "We are delighted to see this exciting and comprehensive body of work now published in a leading peer-reviewed journal," said Dr James Garner, Chief Executive Officer of Kazia. "The data supports our decision last year to in-license EVT801, and clearly points to the future development strategy for the drug. Our collaboration with the Evotec team has already been extremely fruitful, and we look forward to continuing to work together on this very promising drug candidate." The publication may be accessed via the journal website at . Phase I Clinical Trial Progressing EVT801 is currently the subject of an ongoing phase I clinical trial as monotherapy in patients with advanced solid tumors (NCT05114668). The study is progressing as planned, with patients currently being dosed within the anticipated therapeutic range. It is expected that initial data from this study will be available in 1H CY2023. For More Information, Please Contact:- Jane Lowe IR Department [email protected] Phone: +61 411 117 774 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 II study in glioblastoma reported promising signals of efficacy in 2021, and a pivotal study for registration, 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 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 compelling evidence of synergy with immuno-oncology agents. A phase I study commenced recruitment in November 2021. For more information, please visit or follow us on Twitter @KaziaTx. About IUCT-Oncopole The IUCT-Oncopole, a cancer care, research and training center in Toulouse, combines the expertise of 1,800 professionals on a single site labeled "Comprehensive Cancer Center". It combines several state-of-the-art clinical facilities for the treatment of cancer with a world-class research infrastructure, on an integrated campus that brings together public and private stakeholders, including industrial partners. The IUCT-Oncopole, which includes the Claudius Regaud Institute (ICR) and several teams from the Toulouse University Hospital, treats more than 10,000 new patients every year, and more than one in eight patients is enrolled in clinical studies. Visit for more. This document was authorized for release to the ASX by James Garner, Chief Executive Officer, Managing Director. 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. Such statements are based on Kazia's 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 the 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 SEC. 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

New findings suggest that many of the mutations in cancer may simply be setting in stone a path already forged by the tumor stem cell's aberrant dialogue with its surroundings. What drives tumor growth? Is it a few rogue cells imposing their will upon healthy tissue, or diseased tissue bringing out the worst in otherwise peaceable cells? Or is it a back-and-forth, a dialogue between the two? According to a new study, it may be the latter, at least when it comes to the progression of one common skin cancer. Researchers found that a single mutated gene in an otherwise healthy stem cell can kick off an increasingly deviant feedback loop of miscommunication between the cancerous stem cell and its surrounding tissue, fueling the development of a malignant tumor. The findings suggest that many of the mutations in cancer may simply be setting in stone a path already forged by the tumor stem cell's aberrant dialogue with its surroundings. If these results, published in Nature, prove broadly applicable, the findings could pave the way for novel approaches to treating a range of cancers. "It's not just that cancer molds the microenvironment, or that the environment affects the tumor," says first author Shaopeng Yuan, a graduate student in the laboratory of Elaine Fuchs at The Rockefeller University. "Our study shows that there is crosstalk between the microenvironment and the stem cells in tumors. They communicate with each other and create a loop of tumor-promoting factors." Spotlight on squamous cell carcinoma At the heart of almost every tumor is a small subset of cancer stem cells. Resistant to chemotherapy and immunotherapy, these malignant seeds are the cells responsible for keeping the tumor alive and are key players in the process that turns benign growths into metastatic disease. And behind many cancer stem cells, including those of skin, pancreatic, lung, and colorectal cancers, is a RAS gene that, when mutated, allows tissue stem cells to ignore normal environmental signals and deviate from their natural course, promoting out-of-control tissue growth. To better understand the finer points of that interaction, Yuan and colleagues turned their attention to squamous cell carcinoma, a skin cancer linked to RAS mutations. The team started off by inducing mutant HRAS (the member of the RAS family most common in skin cancers) in individual skin stem cells, and monitoring how the cancerous stem cells interacted with the surrounding tissue. "Over time, the dialogue between the cancer stem cell and its microenvironment became more and more aberrant," Fuchs says. "As we deciphered the dialogue, we realized that the miscommunication between the stem cell and its microenvironment resulted in the activation of much the same pathway that is active in the corresponding human cancers that harbor a high mutational burden." This observation raised an intriguing possibility. Perhaps many cancer mutations do not set the course of a disease so much as lock it in place, affirming a malignant progression already determined by aberrant crosstalk between a cancer stem cell and its microenvironment. A surprising role for leptin signaling Further investigating how the cancer stem cell changed as it confronted this new self-imposed malignant tumor microenvironment, the team realized that the invasive cancer stem cells had unexpectedly begun to express the leptin receptor, Lepr. A hormone produced by fat cells and linked to obesity, leptin seemed out of place in non-obese mice carrying non-fatty tumors. Lepr is not expressed in normal epithelium and rarely seen in benign tumor cells. Here it showed up unexpectedly in the cancer stem cells of the advanced stage of the tumor, known as squamous cell carcinoma (SCC). Yuan used CRISPR technology to show that Lepr and leptin receptor signaling was essential for progression from the benign to malignant state. But where was the leptin coming from? There was no apparent increase in fat cells that would explain the leptin and neither the benign growths, the advanced tumor cells, or the tumor microenvironment seemed to express the leptin gene. Yet, the malignant tumor expressing the leptin receptor greatly benefited from the presence of leptin -- the more leptin, the faster it grew. The team began to wonder whether leptin that normally circulates in the bloodstream was arriving at the tumor via the blood vessels that bring nutrients and other factors to the tumor. Through a series of experiments, they provided compelling evidence that this was the case. Moreover, they went on to demonstrate that Lepr/leptin signaling within the cancer stem cells stimulated many of the pathways known to be hyperactivated in cancers, including the PI3-kinase, AKT and mTOR pathways. Taken together, the researchers unraveled how a single oncogene could trigger a self-perpetuating series of miscommunications between the stem cell and its environment leading to malignancy. The team is now investigating ways to block the leptin receptors in tumors as in doing so, it could throw a molecular monkey wrench into the vicious loop and derail the cancer. "The leptin receptor/leptin crosstalk between cancer stem cells and the microenvironment drives a positive feedback loop that fuels malignancy," Yuan says. "If we block this loop, which is a major pathway driving tumor progression, perhaps we can block tumor progression." Squamous cell carcinomas affect not only skin, but also esophagus, head and neck, lung and other epithelial tissues and, together, comprise the sixth most common cancer world-wide. But the implications of the findings extend beyond this particular cancer. Cancer biologists generally assume that the changes in gene expression that drive tumor progression are the result of many accumulating mutations within a cell, but from a stem cell biologist's view, this work shows how a single oncogenic mutation can set events in motion that will drive cancer forward by aberrant exchange with the tumor microenvironment, independent of subsequent mutations. "Our study shows that one oncogenic mutation can hijack a pathway and achieve the same thing as many cumulative mutations," Yuan says. "We are always looking for mutations, but we must not forget to think about how to stop signaling pathways that drive tumor growth."