Lustgarten Foundation

Preclinical Study Highlight the Potential of Elraglusib in Overcoming FOLFIRINOX-induced Chemoresistance Through Downregulation of Epithelial to Mesenchymal Transition (EMT)Initial Data Demonstrates Early Evidence of Increased Clinical Activity of Combining FOLFIRINOX with Elraglusib and Losartan in Patients with Untreated Metastatic Pancreatic Ductal Adenocarcinoma (PDAC)Deep, Durable Responses Observed in 3/6 patients with Extensive Liver Metastases CHICAGO and FORT WORTH, Texas, Sept. 16, 2024 (GLOBE NEWSWIRE) -- Actuate Therapeutics, Inc. (NASDAQ: ACTU) (“Actuate” or the “Company”), a clinical-stage biopharmaceutical company, focused on developing therapies for the treatment of high-impact, difficult-to-treat cancers through the inhibition of glycogen synthase kinase-3 beta (GSK-3β), announced data from the safety cohort of an ongoing Phase 2 trial of FOLFIRINOX in combination with elraglusib and losartan for untreated metastatic pancreatic adenocarcinoma at the American Association for Cancer Research (AACR) Special Conference on Advances in Pancreatic Cancer Research taking place on September 15-18, 2024, in Boston, Massachusetts. “We are encouraged by the data presentation at this year’s AACR’s Special Conference underscoring elraglusib’s potential in addressing critical challenges in pancreatic cancer treatment,” said Daniel Schmitt, President & Chief Executive Officer of Actuate. “These initial findings provide early clinical evidence that elraglusib may overcome a key chemoresistance mechanism associated with FOLFIRINOX thus enhancing the effectiveness of the combination therapy.” The Phase 2 trial (NCT05077800) is an open-label, multi-arm, non-comparator study of FOLFIRINOX in combination with elraglusib and losartan for the treatment of adult patients with untreated metastatic pancreatic adenocarcinoma. The primary objectives of the trial are to determine the safety, tolerability, and progression-free survival of the combination therapy. The trial will enroll up to 70 treatment-naïve metastatic pancreatic adenocarcinoma patients. Actuate Therapeutics supports this trial by supplying the study drug, elraglusib. The Lustgarten Foundation is providing funding support for this study through a research grant. “We are excited by the promising safety profile and initial evidence of clinical activity demonstrated by the combination of FOLFIRINOX, elraglusib and losartan in this study,” said Colin Weekes, MD, Ph.D., Director of Medical Oncology Research for Pancreatic Cancer, Massachusetts General Hospital, and the study’s Principal Investigator. “The synergy observed with these drugs suggests that this combination could offer a novel and effective therapeutic strategy for patients with metastatic pancreatic cancer.” Poster presentation details Abstract: C073 Title: “FOLFIRINOX with Glycogen Synthase Kinase-3 Beta (GSK-3β) Inhibitor Elraglusib and Transforming Growth Factor- β (TGFβ) Inhibitor Losartan in Untreated Metastatic Pancreatic Ductal Adenocarcinoma (PDAC): Interim analysis of safety cohort.”Presenting Author: Priyadarshini Pathak, MD, Medical Oncologist, Massachusetts General Hospital Session date: Tuesday, September 17, 6:45-9 p.m. ETLocation: Westin Copley Place The abstract is available online and the poster will be available on Actuate’s website after the AACR Meeting. About Actuate Therapeutics, Inc. Actuate is a clinical-stage biopharmaceutical company focused on developing therapies for the treatment of high-impact, difficult-to-treat cancers. Actuate’s lead investigational drug product, elraglusib (a novel GSK-3β inhibitor), targets molecular pathways in cancer that are involved in promoting tumor growth and resistance to conventional cancer drugs such as chemotherapy including several DDR pathways. Elraglusib is designed to act as a mediator of anti-tumor immunity through the inhibition of NF-kB and regulates multiple immune checkpoints and immune cell function. For additional information, please visit the Company’s website at http://www.actuatetherapeutics.com. About Massachusetts General HospitalMassachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. MGH is a founding member of the Mass General Brigham healthcare system. Forward-Looking Statements This press release contains forward-looking statements about us, including our clinical trials and development plans, and our industry. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “ongoing,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would,” or the negative of these terms or other comparable terminology are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. All statements, other than statements related to present facts or current conditions or of historical facts, contained in this press release are forward-looking statements. Accordingly, these statements involve estimates, assumptions, substantial risks and uncertainties which could cause actual results to differ materially from those expressed in them, including but not limited to that clinical and preclinical drug development involves a lengthy and expensive process with uncertain timelines and outcomes, results of prior preclinical studies and early clinical trials are not necessarily predictive of future results, and elraglusib may not achieve favorable results in clinical trials or preclinical studies or receive regulatory approval on a timely basis, if at all; that we may not successfully enroll additional patients or establish or advance plans for further development; that elraglusib could be associated with side effects, adverse events or other properties or safety risks, which could delay or preclude regulatory approval, cause us to suspend or discontinue clinical trials or result in other negative consequences; our reliance on third parties to conduct our non-clinical studies and our clinical trials; our reliance on third-party licensors and ability to preserve and protect our intellectual property rights; that we face significant competition from other biotechnology and pharmaceutical companies; and our ability to fund development activities. . In addition, any forward-looking statements are qualified in their entirety by reference to the factors discussed under the heading “Risk Factors” in our final prospectus filed with the SEC on August 13, 2024 pursuant to Rule 424(b)(4) under the Securities Act with respect to our Registration Statement on Form S-1 (File No. 333-279734) and other filings with the SEC. Because the risk factors referred to above could cause actual results or outcomes to differ materially from those expressed in any forward-looking statements made by us or on our behalf, you should not place undue reliance on any forward-looking statements. Further, any forward-looking statement speaks only as of the date on which it is made. New factors emerge from time to time, and it is not possible for us to predict which factors will arise. In addition, we cannot assess the impact of each factor on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements. Unless legally required, we do not undertake any obligation to release publicly any revisions to such forward-looking statements to reflect events or circumstances after the date of this press release or to reflect the occurrence of unanticipated events. Investor Contact Mike Moyer Managing Director LifeSci Advisors, LLC mmoyer@lifesciadvisors.com

Researchers have developed a 3D genomic profiling technique to identify small precancerous lesions in the pancreas -- called pancreatic intraepithelial neoplasias (PanINs) -- that lead to one of the most aggressive, deadly pancreatic cancers. Researchers at the Johns Hopkins Kimmel Cancer Center's Sol Goldman Pancreatic Cancer Research Center have developed a 3D genomic profiling technique to identify small precancerous lesions in the pancreas -- called pancreatic intraepithelial neoplasias (PanINs) -- that lead to one of the most aggressive, deadly pancreatic cancers. Published May1 in Nature, the results provide the most detailed 3D map of precancerous lesions in the human pancreas to date, laying a foundation for future early detection of pancreatic ductal adenocarcinoma (PDAC) and other types of pancreatic cancer. "Not many people actually develop pancreatic cancer, so we were shocked to find a lot of precancer, or PanINs, within the normal regions of the pancreas," says Laura Wood, M.D., Ph.D., associate professor of pathology and oncology at the Kimmel Cancer Center and the Johns Hopkins University School of Medicine and one of the study's senior authors. "This research highlights what we don't yet know about normal aging and raises fundamental questions about how cancer arises in the human pancreas." The research was co-led by Alicia Braxton, D.V.M., Ph.D., a postdoctoral fellow at the Johns Hopkins University School of Medicine, and Ashley Kiemen, Ph.D., an assistant professor of pathology at the medical school. Because of their small size, PanINs are challenging to detect and cannot be identified by a typical radiology examination. In the clinic, this often means that by the time patients are diagnosed with cancer, such as PDAC, the cancer already has reached an advanced stage and metastasized to other organs. Existing 2D histological staining methods, during which tissue is thinly sliced, stained and examined under a microscope, provide only a limited view of PanINs, leaving researchers in the dark about their origins and how they lead to cancer. To better characterize PanINs, the researchers developed a 3D approach. After thinly slicing and staining tissue from 38 normal pancreatic samples onto hundreds of sequential 2D slides, the researchers developed CODA, a machine-learning pipeline, to analyze and reconstruct the slide images into digital 3D images. The 3D reconstructions revealed complex networks of interconnected PanINs with an average overall burden of 13 PanINs per cubic centimeter, and a range of from 1 to 31 PanINs per cubic centimeter. Patients with PDAC in other regions of their pancreas seemed to have a higher PanIN burden than those with nonductal disease, although it was not statistically significant. The researchers further investigated eight of the samples via 3D-guided microdissection and DNA sequencing of specific PanINs. Genomic analysis revealed that the networks were made up of genetically distinct PanINs driven by different gene mutations, such as mutations in the cancer-causing gene Kirsten rat sarcoma virus (KRAS), which is found in most pancreatic cancers. The finding that multiple precancerous lesions arose from independent mutations is something that hasn't yet been seen in other organs, says Wood, "but now that we know that PanINs are there, we can work on targeting them, such as through KRAS." Although CODA is not yet usable in a diagnostic setting, among its advantages is that it can be applied to any tissue, disease or model organism, says Kiemen. "This is just the beginning," she says. "We want to continue to investigate what this means in the context of other organ tissues. If normal tissue has thousands of PanINs, then how do we identify which ones are clinically relevant to disease and which ones are not?" "One of the ways we can make a difference for the largest number of people with cancer is through prevention, and better understanding the early precursors to cancer through detailed and anatomic molecular maps is the first step," adds Wood. "Until you look in 3D, you don't know what you're missing." The study's other co-authors include Mia Grahn, André Forjaz, Jeeun Parksong, Jaanvi Mahesh Babu, Jiaying Lai, Lily Zheng, Noushin Niknafs, Rebecca Reichel, Sarah Graham, Alexander Damanakis, Catherine Fischer, Stephanie Mou, Cameron Metz, Julie Granger, Xiao-Ding Liu, Niklas Bachmann, Yutong Zhu, YunZhou Liu, Cristina Almagro-Pérez, Ann Chenyu Jiang, Jeonghyun Yoo, Bridgette Kim, Scott Du, Eli Foster, Jocelyn Hsu, Paula Andreu Rivera, Linda Chu, Fengze Liu, Elliot Fishman, Alan Yuille, Nicholas Roberts, Elizabeth Thompson, Robert Scharpf, Rachel Karchin, Ralph Hruban, Pei-Hsun Wu, and Denis Wirtz of Johns Hopkins. Other authors were from the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, and the Institute of Cancer Research at the Henan Academy of Innovations in Medical Science in Zhengzhou, China. The work was supported by multiple grants from the National Cancer Institute at the National Institutes of Health, the Sol Goldman Pancreatic Cancer Research Center, Lustgarten Foundation, Break Through Cancer, the Buffone Family Gastrointestinal Cancer Research Fund, the Allegheny Health Network -- Johns Hopkins Cancer Research Fund, the American Association for Cancer Research (AACR)-Bristol Myers Squibb Midcareer Female Investigator Grant, the Rolfe Pancreatic Cancer Foundation, the Joseph C. Monastra Foundation for Pancreatic Cancer Research, the Gerald O Mann Charitable Foundation (trustees Harriet and Allan Wulfstat), S. Wojcicki and D. Troper, the Lustgarten Foundation-AACR Career Development Award for Pancreatic Cancer Research (in honor of Ruth Bader Ginsburg) and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-1-067 and 2021-1-I2M-018). Kiemen, Hruban, Wu, Wirtz and Wood filed a patent June 24, 2022, for the 3D genomic profiling technique. This relationship is managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.

A novel treatment for leukemias and lymphomas that arise from immune system T cells was found to be effective at killing these cancers in mice bearing human T-cell tumors. A novel treatment for leukemias and lymphomas that arise from immune system T cells, developed by investigators at the Johns Hopkins Kimmel Cancer Center and its Ludwig Center and Lustgarten Laboratory, was found to be effective at killing these cancers in mice bearing human T-cell tumors. The therapy, an antibody-drug conjugate (ADC), combines an antibody that targets a protein called TRBC1 expressed on the surface of T-cell cancers with an anti-cancer drug, called SG3249. The ADC works by using the antibody to seek out the cancer cells that express TRBC1. Then, those cancer cells ingest the ADC, where SG3249 is released and kills the cancer cells. A description of the work was published March 27 in Nature. Each year, about 100,000 patients worldwide are affected by T-cell leukemias and lymphomas. Adults with relapsed T-cell cancers have limited therapeutic options and five-year survival rates of 7-38%. "Developing treatments for T-cell leukemias and lymphomas is much more difficult than for leukemias and lymphomas arising from immune system B cells," explains senior study author Suman Paul, M.B.B.S., Ph.D., an assistant professor of oncology at the Johns Hopkins University School of Medicine. Effective therapies for B-cell cancers wipe out both cancerous and noncancerous B cells, but patients still do well even without the immune system B cells that help fight infections. However, if similar approaches are used and a treatment wipes out both normal and cancerous T cells, it would leave patients without a functioning immune system and at high risk of dying from infections. "Not much drug development has happened in this space of T-cell leukemias and lymphomas," Paul says. "We need new therapies for these cancers, but whatever therapies we develop in the space have to be cancer-specific. We have to preserve some of the normal T cells and wipe out cancerous T cells at the same time." T-cell cancers express either TRBC1 or TRBC2, while normal T cells express a mix of TRBC1 and TRBC2. Therefore, selective targeting of TRBC1 can potentially eradicate the normal and cancerous T cells expressing TRBC1 while preserving normal T cells expressing TRBC2. A recent clinical trial conducted elsewhere attempted to target TRBC1 cancers using chimeric antigen receptor (CAR) T-cell therapy. These CAR T cells are genetically engineered T cells that bind to and kill TRBC1 cells. CAR T-cell therapies are FDA-approved treatment options used in several B-cell cancers. However, after administering the TRBC1-targeting CAR T cell therapy in human patients, trial investigators reported that the CAR T cells were not persisting inside the patients. Such persistence is required for effective cancer cell-killing. Interested to understand why, Paul and colleagues found that the CAR T cells targeting TRBC1 could be killed by normal T cells, limiting their persistence. This lack of CAR T-cell persistence led the team to try TRBC1 targeting with the use of antibody-drug conjugates. Paul and colleagues tried two different formulations of ADCs in mouse models of T-cell cancers. After a single injection of one formulation of the treatment, the cancers initially regressed but then recurred. After a single treatment with the anti-TRBC1-SG3249 ADC combination, investigators observed signs of cancer elimination within seven days and the cancers were eventually undetectable, with no recurrences. "The tumors didn't come back, and we followed the mice for more than 200 days," Paul explains. The treatment was able to eliminate the cancer while preserving half of the remaining normal T cells. "The residual normal T cells should be sufficient to maintain some immune system protection against infectious diseases," Paul says. "Witnessing the successful elimination of T-cell cancers while sparing normal T cells in preclinical models was truly gratifying," adds Jiaxin Ge, a co-author of the study and third-year Ph.D. student in the Ludwig Center. "We believe this approach has the potential to address a critical unmet need in oncology, and we're committed to advancing it through further research." Tushar Nichakawade, first author on the study and a fourth-year Ph.D. student at the Ludwig Center, says, "There are so many lessons to learn from the clinic and it has been exciting to be a part of the iterative process of drug discovery. Every therapy has its pros and cons, but the preclinical efficacy of our ADC gives me hope that it can make a difference for patients suffering from these terrible cancers." Investigators are now working with an industry partner to conduct early-phase safety and efficacy trials in human patients. The study's co-authors were Brian J. Mog, Bum Seok Lee, Alexander H. Pearlman, Michael S. Hwang, Sarah R. DiNapoli, Nicholas Wyhs, Nikita Marcou, Stephanie Glavaris, Maximilian F. Konig, Sandra B. Gabelli, Evangeline Watson, Cole Sterling, Nina Wagner-Johnston, Sima Rozati, Lode Swinnen, Ephraim Fuchs, Drew M. Pardoll, Kathy Gabrielson, Nickolas Papadopoulos, Chetan Bettegowda, Kenneth W. Kinzler, Shibin Zhou, Surojit Sur and Bert Vogelstein of Johns Hopkins. The work was supported in part by The Virginia and D.K. Ludwig Fund for Cancer Research, Lustgarten Foundation for Pancreatic Cancer Research, Commonwealth Fund, Bloomberg~Kimmel Institute for Cancer Immunotherapy, Bloomberg Philanthropies and the National Institutes of Health Cancer Center Support Grant P30 CA006973. Paul was supported by the National Cancer Institute (grant K08CA270403), the Leukemia Lymphoma Society Translation Research Program Award, the American Society of Hematology Scholar Award and the Swim Across America Translational Cancer Research Award.