MLL1

– Combination of ziftomenib and imatinib shows robust and durable antitumor activity in imatinib-sensitive (1L) and imatinib-resistant (2L/3L) GIST models – – Proof-of-concept study of ziftomenib plus imatinib in patients with advanced GIST after imatinib failure to begin in 1H 2025 – SAN DIEGO, Oct. 24, 2024 (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 reported preclinical data supporting the development of the Company’s menin inhibitor, ziftomenib, for the treatment of advanced gastrointestinal stromal tumors (GIST). The new findings are being presented at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona. A copy of the poster, entitled “Menin Inhibitor Ziftomenib Synergizes with Imatinib in Tyrosine Kinase Inhibitor (TKI)-Resistant Gastrointestinal Stromal Tumor Models,” is available in the Posters and Presentations section on Kura’s website. “Kura has generated a substantial body of preclinical data that support potential for ziftomenib in combination with KIT inhibitors for the treatment of patients with advanced GIST,” said Francis Burrows, Ph.D., Senior Vice President, Translational Research. “Our results indicate that the combination of ziftomenib and imatinib acts via a synthetic lethal mechanism through which ziftomenib targets an epigenetic vulnerability of GIST tumors, creating potent synergy even with KIT inhibitors that are otherwise inactive as monotherapy. Indeed, the activity of ziftomenib appears to be agnostic to the mutational status of KIT in GIST, suggesting an opportunity to explore the combination for all patients, even in the frontline setting.” The combination of ziftomenib and imatinib unexpectedly showed robust and durable antitumor activity in both imatinib-sensitive and imatinib-resistant GIST patient-derived xenograft models, and in all cases was significantly superior to imatinib monotherapy. Mechanistically, the data reveal a KIT-dependent mechanism, with ziftomenib and imatinib combining to sharply reduce KIT expression and/or activity, effectively silencing both the ERK and AKT/mTOR signaling pathways and driving robust cell cycle arrest and apoptosis. Given that imatinib is well established as the frontline standard of care in patients with GIST, and that generic versions are available, imatinib represents a promising combination partner for ziftomenib. In August 2024, Kura announced clearance by the U.S. Food and Drug Administration (FDA) of the Investigational New Drug (IND) application for ziftomenib for the treatment of advanced GIST. The Company is now preparing to initiate a proof-of-concept study evaluating ziftomenib and imatinib in patients with advanced GIST after imatinib failure in the first half of 2025. For more information regarding the study, please visit www.clinicaltrials.gov (identifier: NCT06026410). About GIST Gastrointestinal stromal tumors (GIST) are the most common form of sarcoma, characterized as KIT-dependent solid tumors. Despite the successful disease control achieved with imatinib in advanced GIST patients, most patients eventually progress due to acquired secondary KIT mutations. TKIs such as sunitinib can target imatinib-resistant genotypes and are approved in later lines, but response rates and long-term outcomes are modest, so new therapeutic options are needed. Previously published data show that the menin-MLL complex regulates KIT expression in GIST cells, and menin inhibitors display additive therapeutic activity in combination with imatinib in imatinib-sensitive GIST models1. About Ziftomenib Ziftomenib is a potent, selective and oral menin inhibitor currently in development for the treatment of genetically defined AML patients with high unmet need. In April 2024, ziftomenib received Breakthrough Therapy Designation (BTD) by the FDA for the treatment of relapsed/refractory (R/R) NPM1-mutant acute myeloid leukemia (AML) based on data from Kura’s ongoing KOMET-001 clinical trial. Additional information about clinical trials for ziftomenib can be found at kuraoncology.com/clinical-trials/#ziftomenib. 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, a once-daily, oral drug candidate targeting the menin-KMT2A protein-protein interaction, has received BTD for the treatment of R/R NPM1-mutant AML. Kura has completed enrollment in a Phase 2 registration-directed trial of ziftomenib in R/R NPM1-mutant AML (KOMET-001). The Company is also conducting a series of clinical trials to evaluate ziftomenib in combination with current standards of care in newly diagnosed and R/R NPM1-mutant and KMT2A-rearranged AML. Kura is evaluating KO-2806, a next-generation farnesyl transferase inhibitor (FTI), in a Phase 1 dose-escalation trial as a monotherapy and in combination with targeted therapies (FIT-001). 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). For additional information, please visit Kura’s website at www.kuraoncology.com and follow us on X and LinkedIn. 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 ziftomenib, potential benefits of combining ziftomenib with appropriate standards of care, and progress and expected timing of the ziftomenib 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, 2024 filed with the SEC on August 8, 2024, which are available at www.sec.gov. 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 SpainExecutive Vice President, Investor Relations &Corporate Communications(858) 500-8833pete@kuraoncology.com Media:Cassidy McClainVice PresidentInizio Evoke Comms(619) 849-6009cassidy.mcclain@inizioevoke.com 1 Hemming ML et al., Cancer Discov. 2022;12:1804-1823.

*仅供医学专业人士阅读参考肿瘤微环境（TME）是由肿瘤细胞及其周围的各种正常细胞共同构成的复杂生态系统，其中免疫细胞、血管细胞、基质细胞等相互作用，影响肿瘤的生长、侵袭和转移。在近年来的肿瘤研究中，针对肿瘤微环境的调控成为一种潜在的治疗策略。传统的体外细胞培养模型往往无法充分模拟体内微环境的复杂性，限制了对肿瘤微环境中复杂相互作用机制的理解。基于CRISPR/Cas9的基因筛查技术能够有效识别调控肿瘤生物学的重要基因，近年来，体内CRISPR筛查发现了一些调控免疫治疗抵抗的靶点，证明了在生理肿瘤微环境中进行基因筛查的重要性。加拿大多伦多大学Housheng Hansen He和Ming-Sound Tsao等人通过比较体外和体内CRISPR筛选结果，他们发现MEN1基因仅在肿瘤微环境中表现出肿瘤生长调节作用，而且具有双重作用，能够在不同免疫环境下通过调节不同免疫细胞的浸润发挥着促癌或抑癌的功能，并揭示其中的调控机制。这一发现强调了体内基因筛选在发现临床药物靶点中的重要性，并为靶向MEN1的治疗策略提供了依据。论文于近日发表在《自然·遗传学》[1]。论文首页截图首先，研究者们设计了一个包含12472个sgRNA的单导向RNA（sgRNA）库，该库靶向317个表观遗传调控因子和657个药物靶标。他们将稳定表达Cas9的A549肺腺癌细胞系用该sgRNA文库进行转导，然后将这些细胞分为两组：一组在体外二维培养皿中培养，另一组通过皮下注射在免疫缺陷型肺癌小鼠模型（NSG）中建立异种移植瘤。研究者对比体外培养细胞与小鼠体内移植瘤的基因筛选结果后发现，MEN1基因在体内筛选中显著富集，而且是体内模型中肿瘤生长的关键基因，而体外模型中并未发现类似效应。具体来说，在体外培养中，MEN1基因缺失对癌细胞增殖没有影响；在体内实验中，MEN1的作用取决于宿主的免疫状况。在免疫缺陷的小鼠中，MEN1缺失显著促进了肿瘤生长，而在免疫健全的小鼠中，MEN1缺失则抑制了肿瘤生长。体内外平行CRISPR筛选发现MEN1在肺癌小鼠体内具有特定的肿瘤调节功能进一步研究揭示了MEN1基因及其编码蛋白menin对肿瘤的调控机制。MLL是一类与急性白血病密切相关的基因，编码表观遗传调控蛋白，这些MLL家族蛋白能够通过修饰染色质结构影响基因的表达。通过RNA测序分析，研究者们发现MEN1缺失会通过改变MLL家族中的关键成员MLL1在染色质上的分布，引起染色质重塑和表观遗传修饰的变化，增加特定基因组区域的H3K4me3修饰。这种表观遗传变化能够激活双链RNA（dsRNA）的表达，引发由线粒体抗病毒信号蛋白（MAVS）和cGAS–STING通路介导的类似病毒感染的免疫反应，从而调节CXCL1、IL33、CXCL8等细胞因子的基因表达和肿瘤生长。结直肠癌、乳腺癌等肿瘤小鼠模型实验结果验证，MEN1缺失会对肿瘤微环境中的免疫细胞浸润产生显著影响。免疫健全的小鼠中，MEN1缺失引起dsRNA激活主要增加CD8+T细胞的浸润，助力抗肿瘤免疫效应；但在免疫缺陷的小鼠中，由于缺乏适应性免疫反应，MEN1缺失引起dsRNA激活后唤不来CD8+T细胞，而是更多地吸引中性粒细胞浸润到肿瘤微环境中，这些中性粒细胞通常被认为促进肿瘤生长和侵袭的推波助澜者之一。MEN1在不同免疫环境下调节不同的免疫细胞，因此兼备双重身份因此，MEN1的缺失能够在不同的免疫环境下产生相反的效果，解释了其在免疫缺陷和免疫健全小鼠中对肿瘤生长的不同影响。此外，药理学研究显示，抑制menin与MLL1相互作用的药物Ziftomenib能够有效抑制乳腺癌小鼠的肿瘤生长，效果与MEN1缺失相似，并且该这种效应依赖于CD8+T细胞的存在，以剂量依赖性的方式增加肿瘤浸润CD8+T细胞数量。研究者们根据RNA测序结果观察到，MEN1缺失的结直肠癌小鼠和MEN1低表达患者的肿瘤中，PD-L1的表达水平显著升高，PD-1表达也有增加趋势。由此他们展开小鼠实验并发现，当Ziftomenib与PD-1抑制剂联合使用时，相比两种任一单药治疗的肿瘤抑制效果都显著增强，表明抑制MEN1可能成为增加免疫疗法疗效的潜在策略。抑制menin与MLL1相互作用有效果，可以与PD-1抑制剂联合使用这项研究表明，MEN1基因在肿瘤生长中的作用依赖于宿主的免疫环境，通过调控肿瘤微环境中免疫细胞的浸润，表现出在不同免疫环境下的促癌和抑癌双重功能，这种现象为理解肿瘤微环境对基因功能的影响提供了新的视角，也为开发基于肿瘤微环境的个性化治疗策略提供了新思路。MEN1及其相关的分子通路可能在未来的肿瘤治疗中发挥重要作用，尤其是在与免疫治疗相结合的策略中，具有广阔的应用前景。------奇点糕近期推出了《2024ASCO年会深度盘点》课程，为大家系统盘点了2024ASCO年会上实体瘤领域的重磅进展，让您在100分钟内迅速深入把握前沿。长按识别下图中的二维码即可购买，购买后您可以在「奇点网小程序」收听，或下载奇点网「医学奇点」苹果客户端收听。如果遇到任何技术问题，大家可以戳我们下图中的客服小伙伴来解决~~参考文献：[1]Su, P., Liu, Y., Chen, T. et al. In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor–microenvironment interactions. Nat Genet 56, 1890–1902 (2024). https://doi.org/10.1038/s41588-024-01874-9本文作者丨张艾迪

SAN DIEGO, Sept. 30, 2024 (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 the publication of its KOMET-001 Phase 1 study manuscript in The Lancet Oncology journal. The paper, entitled “Ziftomenib in relapsed/refractory acute myeloid leukaemia (KOMET-001): results from an open-label, multi-cohort, phase 1a/1b trial,” is now available on The Lancet Oncology website and in the Scientific Manuscripts section on Kura’s website. “The results from the KOMET-001 Phase 1 study are encouraging as they demonstrate meaningful benefit of ziftomenib in NPM1 -mutant acute myeloid leukemia (AML), and publication of these data expands the growing evidence supporting the efficacy and safety of ziftomenib in a disease indication of unmet need,” said Ghayas C. Issa, M.D., assistant professor of Leukemia at The University of Texas MD Anderson Cancer Center. “We are thankful for the patients and their families for their participation in the KOMET-001 trial and for the scientific community who have contributed to this research to advance more tolerable and effective treatment options for AML patients.” The KOMET-001 study is a Phase 1/2 global, open-label, multi-cohort clinical trial evaluating the safety, tolerability and clinical activity of ziftomenib in relapsed/refractory (R/R) AML. In the Phase 1a dose escalation portion, patients received ziftomenib once daily in 28-day cycles and in the Phase 1b dose validation/expansion portion, patients were randomized to two parallel cohorts at 200 mg and 600 mg. As of the data cutoff on August 30, 2023, 83 patients received one or more doses of ziftomenib and the primary objective of this study was to determine the recommended phase 2 dose (RP2D) based on safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary activity. The results demonstrated promising clinical activity with manageable toxicity in heavily pretreated patients including marrow blast reduction, neutrophil and platelet recovery, transfusion independence, and clearance of measurable residual disease. “Our Phase 1 study provided the critical safety and clinical activity data in order to determine the RP2D and support our pivotal Phase 2 registration-directed trial in patients with NPM1 -mutant AML,” said Stephen Dale, M.D., Chief Medical Officer of Kura Oncology. “These data reinforce our commitment to developing novel investigational therapies, including menin inhibitors, to realize the transformative value for patients with acute leukemias. The clinical data generated to date, including the insights gained from this study, demonstrate the potential for ziftomenib to become a cornerstone of AML therapy through monotherapy and combination approaches.” In May 2024, Kura Oncology announced completion of enrollment in the Phase 2 portion of KOMET-001, a registration-directed trial of ziftomenib in patients with R/R NPM1-mutant AML. Enrollment of the 85 patients in Phase 2 was completed in fewer than 16 months and the Company expects to report topline data from the trial in early 2025. About NPM1 -mutant AML AML is the most common acute leukemia in adults and begins when the bone marrow makes abnormal myeloblasts (white blood cells), red blood cells or platelets. Despite the many available treatments for AML, prognosis for patients remains poor and a high unmet need remains. The menin pathway is considered a driver for multiple genetic alterations of the disease, of which NPM1 mutations are among the most common, representing approximately 30% of AML cases. While patients with NPM1 -m AML have high response rates to frontline therapy, relapse rates are high and survival outcomes are poor, with only 30% overall survival at 12 months in the R/R setting. Additionally, NPM1 mutations frequently occur with co-mutations in other disease-associated genes, including FLT3 , DNMT3A and IDH1/2 , with prognosis heavily influenced by the presence of co-occurring mutations. Adult patients with NPM1 -m AML and select co-mutations and/or R/R disease have a poor prognosis, with median overall survival of only approximately 7.8 months in 2 nd line, 5.3 months in 3 rd line, and 3.5 months following the 4 th line 1 . There are currently no FDA-approved therapies targeting NPM1 -m AML. About Ziftomenib Ziftomenib is a novel, once-daily, oral investigational drug candidate targeting the menin-KMT2A/MLL protein-protein interaction for treatment of genetically defined AML patients with high unmet need. In the KOMET-001 Phase 1 study, ziftomenib demonstrated encouraging safety and tolerability with reported events consistent with features and manifestations of underlying disease. Clinical activity of ziftomenib as a monotherapy was optimal at the 600 mg daily dose and a 35% complete remission rate was observed in 20 patients with NPM1 -mutant AML treated at the recommended Phase 2 dose (600 mg). Ziftomenib has received Breakthrough Therapy Designation (BTD) from the U.S. Food and Drug Administration for the treatment of R/R NPM1 -mutant AML. Additional information about clinical trials for ziftomenib can be found at kuraoncology.com/clinical-trials/#ziftomenib . 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, a once-daily, oral drug candidate targeting the menin-KMT2A protein-protein interaction, has received BTD for the treatment of R/R NPM1 -mutant AML. Kura has completed enrollment in a Phase 2 registration-directed trial of ziftomenib in R/R NPM1-mutant AML (KOMET-001). The Company is also conducting a series of clinical trials to evaluate ziftomenib in combination with current standards of care in newly diagnosed and R/R NPM1 -mutant and KMT2A -rearranged AML. Kura is evaluating KO-2806, a next-generation farnesyl transferase inhibitor (FTI), in a Phase 1 dose-escalation trial as a monotherapy and in combination with targeted therapies (FIT-001). 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). For additional information, please visit Kura’s website at and follow us on X and LinkedIn . 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 ziftomenib, potential benefits of combining ziftomenib with appropriate standards of care, and progress and expected timing of the ziftomenib 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, 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: Cassidy McClain Vice President Inizio Evoke Comms (619) 849-6009 cassidy.mcclain@inizioevoke.com ____________________________________ 1 Issa G, et al. Blood Adv 2023;7(6):933-42.