RHEB

Researchers have uncovered a mechanism in the brain that allows cocaine and morphine to take over natural reward processing systems. Mount Sinai researchers, in collaboration with scientists at The Rockefeller University, have uncovered a mechanism in the brain that allows cocaine and morphine to take over natural reward processing systems. Published online in Science on April 18, these findings shed new light on the neural underpinnings of drug addiction and could offer new mechanistic insights to inform basic research, clinical practice, and potential therapeutic solutions. "While this field has been explored for decades, our study is the first to demonstrate that psychostimulants and opioidsengage and alter functioning of the same brain cells that are responsible for processing natural rewards," explains senior author Eric J. Nestler, MD, PhD, Nash Family Professor of Neuroscience, Director of The Friedman Brain Institute, and Dean for Academic Affairs of the Icahn School of Medicine at Mount Sinai, and Chief Scientific Officer of the Mount Sinai Health System. "These findings provide an explanation for how these drugs can interfere with normal brain function and how that interference becomes magnified with increasing drug exposure to ultimately redirect behavior compulsively towards drugs -- a hallmark of addiction pathology." The study focused on identifying convergent mechanisms of addiction in mouse models across two different classes of drugs: cocaine, a psychostimulant, and morphine, an opioid. This groundbreaking work required the amalgamation of a highly interdisciplinary team, organized by Dr. Nestler and long-time collaborator Jeffrey M. Friedman, MD, PhD, Marilyn M. Simpson Professor at The Rockefeller University, Investigator of the Howard Hughes Medical Institute, and co-senior author of the study. Among its members were two biophysicists: Alipasha Vaziri, PhD, Professor of Neuroscience and Behavior at The Rockefeller University and a co-senior author of the study, and Tobias Nöbauer, PhD, Assistant Research Professor at The Rockefeller University and a co-first author of the study. Working closely together, the team employed a suite of cutting-edge tools and methodologies spanning behavioral, circuit, cellular, and molecular domains of neuroscience. Through these innovative efforts, researchers were able to track how individual neurons in a forebrain region called the nucleus accumbens respond to natural rewards like food and water, as well as to acute and repeated exposure to cocaine and morphine in a cell-type-specific manner. They discovered a largely overlapping population of cells that respond to both addictive drugs and natural rewards, and demonstrated that repeated exposure to the drugs progressively disrupts the cells' ability to function normally, resulting in behavior being directed toward drug-seeking and away from natural rewards. "By tracking these cells, we show that not only are similar cells activated across reward classes, but also that cocaine and morphine elicit initially stronger responses than food or water, and this actually magnifies with increasing exposure," notes co-first author Caleb Browne, PhD, a former Instructor in Dr. Nestler's lab who is now a Scientist in the Campbell Family Mental Health Research Institute at the Centre for Addiction and Mental Health (CAMH) in Toronto. "After withdrawal from the drugs, these same cells exhibit disorganized responses to natural rewards in a manner that may resemble some of the negative affective states seen in withdrawal in substance use disorder." Moreover, the research team identified a well-established intracellular signaling pathway -- mTORC1 -- that facilitates the disruption of natural reward processing by the drugs. As part of that discovery, investigators found a gene (Rheb) that encodes an activator of the mTORC1 pathway that may mediate this relationship, potentially providing a novel therapeutic target for future discovery in a field of medicine that currently offers few effective treatments. To that end, the research team plans to dig deeper into the cellular biology behind addiction neuroscience to better characterize molecular pathways that could be critical to basic research and, eventually, clinical practice. "Through our work we have also established a landmark dataset that integrates drug-induced brain-wide neural activation with input circuit mapping from the nucleus accumbens, which could be useful to the broad scientific community conducting substance use disorder research," says Bowen Tan, the other co-first author of the study, and a graduate student in the laboratory of Dr. Friedman. "We've known for decades that natural rewards, like food, and addictive drugs can activate the same brain region," says Dr. Friedman. "But what we've just learned is that they impact neural activity in strikingly different ways. One of the big takeways here is that addictive drugs have pathologic effects on these neural pathways, that are distinct from, say, the physiologic response to eating a meal when you are hungry or drinking a glass of water when you are thirsty." "A major part of our ongoing research will be directed to defining how the flow of multimodal information is incorporated into value computations in brain cells and how that crucial mechanism enables drugs to overtake the processing of natural rewards, leading to addiction," says Dr. Nestler.

– Meaningful antitumor activity observed in recurrent/metastatic HRAS mutant HNSCC, including CR – – Data validate activity of farnesyltransferase inhibitors and support rapid advancement of KO-2806 into combinations with targeted therapies in large solid tumor indications – – Results to be presented in late-breaking oral session at 2023 ESMO Congress on Saturday – SAN DIEGO, Oct. 17, 2023 (GLOBE NEWSWIRE) -- Kura Oncology Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer, today announced results from its registration-directed AIM-HN study of tipifarnib in patients with HRAS mutant head and neck squamous cell carcinoma (HNSCC) whose disease is recurrent or metastatic and has progressed after prior therapy. These clinical results are being featured during a late-breaking oral session at the 2023 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain, in a presentation titled, “A phase 2 study evaluating tipifarnib in mHRAS, recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) (AIM-HN study).” The abstract is now available on the ESMO website and the presentation will be available in the Posters and Presentations section on Kura’s website at the start of the poster session on Saturday, October 21, 2023 at 10:15AM CEST. As of the data cutoff on June 15, 2023, 59 patients with R/M HRAS mutant HNSCC were enrolled, of whom 50 had high HRAS mutant variant allele frequency (VAF)1 and 38 were evaluable for efficacy. The following table compares response assessed between the investigators and the independent review facility (IRF), in the modified intent to treat (mITT) high VAF population2. Investigator Assessment (n=50) Independent Review Facility (n=50) Best Overall Response, n (%) Confirmed Complete Response (CR) 1 (2)​ 1 (2)​ Confirmed Partial Response (PR) 14 (28)​ 9 (18)​ Stable Disease (SD) 17 (34)​ 14 (28)​ Progressive Disease (PD) 6 (12)​ 14 (28)​ Not Evaluable (NE) 12 (24)​ 12 (24)​ ORR, n (%) [95% CI] ​ 15 (30) [0.18, 0.45]​ 10 (20) [0.10, 0.34]​ mDoR, months [95% CI]​ 5.6 [3.88, 9.23]​ 6.5 [3.88, -]​ mPFS, months [95% CI]​ 3.7 [2.60, 5.55]​ 2.6 [1.87, 4.40]​ *ORR, objective response rate; -, not calculable; mDoR, median duration of response; mPFS, median progression free survival; CI, confidence interval. Both assessments by investigators and IRF observed one patient achieving a CR on treatment. Patients had a median of two prior lines of therapy (range 0-6) in the recurrent/metastatic setting and robust activity was seen in second line treatment and beyond with greater activity observed in the second line versus the third line and subsequent treatments. The ORR in second line treatment was 29% [0.13, 0.51] in the IRF assessment. The ORR for three FDA-approved therapies for the treatment of HNSCC in the second line range from 13-16%. “The results from the AIM-HN study are encouraging as they demonstrate meaningful clinical benefit of tipifarnib in a subset of HNSCC for which there are currently no other targeted therapies in development, and a significant unmet need exists for the population,” said Alan Ho, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center and principal investigator of the study. “We are grateful to the patients and their families for their trial participation and for the scientific community who have contributed to this pivotal research in an effort to impact patients’ lives.” Patients in the AIM-HN trial received tipifarnib at a dose of 600 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles. Tipifarnib was generally well-tolerated with a manageable safety profile. The most common grade 3 or 4 treatment-related adverse events (TRAEs) seen in at least 10% of patients were cytopenias and TRAEs led to discontinuation of treatment in 7% of patients. “We continue to be encouraged by the compelling safety pro activity of tipifarnib as a monotherapy in this difficult-to-treat population of advanced head and neck cancer, supported by our Breakthrough Therapy Designation from the FDA,” said Troy Wilson, Ph.D., J.D., President and Chief Executive Officer of Kura Oncology. “Building on the results of the previous RUN-HN study, these data confirm that, in the proper biological context in which a target protein is obligately farnesylated, FTIs have potential to drive meaningful clinical benefit for patients. With these data in hand, we continue to evaluate in the ongoing KURRENT-HN study whether the combination of tipifarnib and alpelisib has potential to extend the clinical benefit observed in this study to a broader set of HNSCC patients.” “In addition,” Dr. Wilson continued, “we believe these positive results from AIM-HN validate the therapeutic value of farnesyl transferase inhibition as we begin to execute on our clinical development plan for our next-generation FTI, KO-2806, which we will use to target other farnesylated targets such as RHEB and which we believe could become the preferred combination partner for a number of targeted therapies in multiple large solid tumor indications, including KRAS inhibitors in certain solid tumors and tyrosine kinase inhibitors in clear cell renal cell carcinoma.” About AIM-HN AIM-HN is a multicenter, open-label, pivotal study evaluating the efficacy of tipifarnib in HRAS mutant HNSCC. Eligibility criteria include patients with recurrent or metastatic HRAS mutant HNSCC at any VAF level. The primary and key secondary endpoints of this trial include ORR and DoR in the high VAF population. The trial was designed to enroll at least 59 patients with HRAS mutant HNSCC who received prior platinum-based therapy and was closed to enrollment in November 2022. Further details regarding the trial are available at clinicaltrials.gov (NCT03719690). About HNSCC Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide, accounting for more than 500,000 new cases each year. Despite advances in immunotherapy, the prognosis for advanced HNSCC patients remains poor, with an estimated median overall survival of 13-15 months in patients when stratified by PD-L1 expression. Although the anti-epidermal growth factor receptor (EGFR) antibody, cetuximab, was approved more than a decade ago, development of biomarker-directed therapies in HNSCC has been stymied by the limited number of druggable targets in the genomic landscape and the challenge of managing drug refractory, recurrent/metastatic HNSCC. About Kura Oncology Kura Oncology is a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer. The Company’s pipeline consists of small molecule drug candidates that target cancer signaling pathways. Ziftomenib is a once-daily, oral drug candidate targeting the menin-KMT2A protein-protein interaction for the treatment of genetically defined acute myeloid leukemia (AML) patients with high unmet need. Kura is currently enrolling patients in a Phase 2 registration-directed trial of ziftomenib in NPM1-mutant relapsed or refractory AML (KOMET-001). The Company is also conducting a series of studies to evaluate ziftomenib in combination with current standards of care, beginning with venetoclax/azacitidine and standard induction cytarabine/daunorubicin chemotherapy in NPM1-mutant and KMT2A-rearranged newly diagnosed and relapsed/refractory AML (KOMET-007). Tipifarnib, a potent and selective FTI, is currently in a Phase 1/2 trial in combination with alpelisib for patients with PIK3CA-dependent head and neck squamous cell carcinoma (KURRENT-HN). Kura is also preparing to evaluate KO-2806, a next-generation FTI, in a Phase 1 dose-escalation trial as a monotherapy and in combination with other targeted therapies, beginning with ccRCC and KRASG12C-mutant NSCLC (FIT-001). For additional information, please visit Kura’s website at and follow us on Twitter and LinkedIn. Disclosures Memorial Sloan Kettering (MSK) has institutional financial interests related to Kura Oncology. Dr. Ho has financial interests related to Kura Oncology. Forward-Looking Statements This news release contains certain forward-looking statements that involve risks and uncertainties that could cause actual results to be materially different from historical results or from any future results expressed or implied by such forward-looking statements. Such forward-looking statements include statements regarding, among other things, the efficacy, safety and therapeutic potential of tipifarnib, potential benefits of combining tipifarnib with appropriate standards of care, and progress and expected timing of the tipifarnib program and clinical trials. Factors that may cause actual results to differ materially include the risk that compounds that appeared promising in early research or clinical trials do not demonstrate safety and/or efficacy in later preclinical studies or clinical trials, the risk that Kura may not obtain approval to market its product candidates, uncertainties associated with performing clinical trials, regulatory filings, applications and other interactions with regulatory bodies, risks associated with reliance on third parties to successfully conduct clinical trials, the risks associated with reliance on outside financing to meet capital requirements, and other risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs. You are urged to consider statements that include the words “may,” “will,” “would,” “could,” “should,” “believes,” “estimates,” “projects,” “promise,” “potential,” “expects,” “plans,” “anticipates,” “intends,” “continues,” “designed,” “goal,” or the negative of those words or other comparable words to be uncertain and forward-looking. For a further list and description of the risks and uncertainties the Company faces, please refer to the Company's periodic and other filings with the Securities and Exchange Commission (SEC), including the Company’s Form 10-Q for the quarter ended June 30, 2023 filed with the SEC on August 9, 2023, which are available at . Such forward-looking statements are current only as of the date they are made, and Kura assumes no obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. Contacts Investors: Pete De Spain Executive Vice President, Investor Relations & Corporate Communications (858) 500-8833 pete@kuraoncology.com Media: Alexandra Weingarten Senior Manager, Corporate Communications (858) 500-8822 alexandra@kuraoncology.com 1 HRAS variant allele frequency ≥ 20% and treated with at least one dose of tipifarnib 2 One low VAF patient (< 20% VAF) was a responder to treatment

Researchers have discovered a protein that is responsible for controlling cell growth in yeasts. Since humans and yeasts have remarkably similar cellular mechanisms, teasing out the differences presents drug developers with new targets for treatments. Like bacteria, yeasts are found everywhere, even in and around our bodies. And, as with bacteria, you can become infected by yeasts and become ill. Yeasts infect about 150 million people a year and kill about 1.7 million, especially those who are immunocompromised. Yeast cells and human immune system cells rely on surprisingly similar chemical reactions to know when to grow. University of Arizona scientists have identified subtle differences between the two cell types that could help spur the development of antifungal drugs that are able to attack disease-causing yeasts in the body while sparing the immune system. Their findings, published in the journal eLife, not only have implications for drug development, they also provide important insight into the evolution of an ancient growth control pathway found in all multicellular organisms. It is well known in the scientific community that a conglomerate of proteins called TORC1 -- short for Target of Rapamycin kinase Complex 1 -- controls the growth of cells in everything from humans to yeasts. But researchers have now identified and named the protein that triggers this process in yeasts -- a nutrient sensor and TORC1 regulator they named Ait1. When working normally, Ait1 shuts down TORC1 in yeasts when cells are starved for nutrients, blocking cell growth. "Ait1 is kind oflike a hand holding TORC1 in place, with a finger that reaches over the top and flicks TORC1 on and off depending on how many nutrients a cell has," said study co-author Andrew Capaldi, an associate professor in the UArizona Department of Molecular and Cellular Biology and BIO5 Institute member. The Capaldi Lab is interested in determining how cells sense stress and starvation and then decide how fast to grow. Understanding how TORC1 is triggered in different organisms is important for developing treatments for a wide variety of diseases. TORC1 was originally discovered in yeast, but it is also critical for the activation of cells in the human immune system to mount a response. When TORC1 isn't working as it should, it can trigger the development of cancer, diabetes and various neurological disorders including epilepsy and depression. "If TORC1 is too active, it can give rise to cancer or epilepsy. If it's underactive, then it can cause depression," Capaldi said. "We call this Goldilocks regulation." But the fact that human bodies depend on the same TORC1 pathway as yeast presents a problem. Capaldi said if scientists develop drugs that inhibit the growth of disease-causing yeasts by controlling TORC1, "we are in big trouble since TORC1 also controls the growth of human immune cells and more." "As an example, you can block the growth of yeast very easily using rapamycin -- a drug that binds directly to and inhibits TORC1 -- so that would fight any infection well," Capaldi said. "However, that very same drug is regularly used in transplant patients to suppress their immune system, so that would be a disaster." The researchers found that while the TORC1 pathway is very similar in yeast and humans, humans don't rely on Ait1 to regulate TORC1. So, drugs that specifically target Ait1 should inhibit the growth of yeast and not human immune cells. Ait1 has only evolved in the last 200 million years, which is relatively recent in evolutionary terms. About 200 million years ago a TORC1 regulator called Rheb seems to have disappeared from the cells of various organisms exactly when Ait1 evolved. "We showed that some of the ancient TORC1 regulators found in humans (including Rheb) have been lost in the same yeasts that gained Ait1 200 million years ago," Capaldi said. "These same ancient regulators have also been lost in the evolution of other single-celled organisms, including many parasites and plants. So, it is very likely that other single-celled organisms gained new regulators -- similar to Ait1 -- of their own. Now people can go out and look for them, as they will also be good drug targets." Capaldi co-authored the study with Xiangxia Luo, a research specialist in the Capaldi Lab, and two UArizona alumni who were the study's lead authors -- Ryan Wallace, who earned a doctorate degree in biochemistry and molecular biology in 2021 and is now a scientist for Aviva Systems Biology Corporation in San Diego, and Eric Lu, who earned bachelor's degrees in molecular and cellular biology and biochemistry in 2021 and is now pursuing a doctoral and medical degree at Washington University. The researchers have filed a patent for their discovery as a target for antifungal compounds through Tech Launch Arizona, the university office that commercializes university innovations.