PIP4K2C

LRK-A drives monotherapy anti-tumor activity, including complete tumor regressions, in CRC patient samples and an in vivo model IND-enabling studies are under way; Larkspur is moving rapidly toward clinical development March 28, 2024 (GLOBE NEWSWIRE) -- Larkspur Biosciences, a company pioneering a new wave in cancer therapy by targeting cancer-intrinsic drivers of immune evasion, announced that it will present positive preclinical efficacy data for LRK-A, Larkspur’s novel, lead investigational therapy targeting the lipid kinase PIP4K2C, in primary human tumor samples and an in vivo model of colorectal cancer (CRC). The data will be featured in a poster presentation at the 115th Annual Meeting of the American Association for Cancer Research (AACR 2024) in San Diego, CA. “Larkspur Biosciences pursues novel targets inside the cancer, like PIP4K2C, that prevent the immune system from seeing and attacking it. Our data at AACR 2024 demonstrate the potential of targeted PIP4K2C degradation to uncloak the tumor and support the advancement of our PIP4K2C degrader program as a monotherapy to treat CRC and other solid tumors,” said Catherine Sabatos-Peyton, PhD, CEO of Larkspur Biosciences. “Using LarkXCRC, our proprietary bioinformatics platform, Larkspur developed a patient biomarker strategy to select the patients most likely to respond to LRK-A. This strategy enables the design of clinical trials that are smaller, faster, and have a higher probability of success.” CRC is the second leading cause of cancer-related deaths in the U.S.; in people under the age of 50, CRC is the top cause of cancer mortality in men and second cause in women1. Larkspur aims to shift the treatment paradigm – which hasn’t meaningfully changed in decades – by effectively activating the immune system against tumors by targeting PIP4K2C. “PIP4K2C is part of the ‘dark kinome’ – the approximately 25% of kinases with unknown or poorly understood functions,” said Nathanael Gray, PhD, professor of chemical and systems biology at Stanford University and co-founder of Larkspur. “My co-founders and I jointly discovered that PIP4K2C acts in both cancer cells and immune cells to get tumor antigens presented to the right immune cells. Lew Cantley discovered that uniquely among the family of PI5P4K isoforms, mice that were germline knockouts of PIP4K2C broke tolerance, a hallmark of key targets that drive cancer immune evasion. Larkspur’s AACR 2024 presentation sheds further light on PIP4K2C by offering key evidence for its role as a cancer-intrinsic driver of immune evasion in both tumor and immune cells, and demonstrating the therapeutic promise of degrading the target in CRC and other solid tumors.” Published Abstract Number: 5574 Title: “Degradation of PIP4K2C by novel bivalent functional degrader LRK-A induces tumor regression in CRC” Session Category / Session Title: Tumor Biology / Tumor-Immune System Cross-Talk Session Date and Time: Tuesday, April 9, 1:30-5:30 pm PDT Location / Poster Board Number: Poster Section 12 / Number 30 Presenter: Eva d’Hennezel, PhD, Director of Immunology, Larkspur Biosciences Larkspur Biosciences is pioneering a new wave in cancer therapy that stops immune evasion where it starts: in the tumor. Larkspur’s approach targets cancer-intrinsic factors that tumors use to escape immune detection and control to develop new treatment options for patients who cannot be helped by current therapies. The company is advancing first-in-class programs designed to eliminate tumor “bottlenecks” that drive immune evasion in colorectal cancer (CRC) and beyond. LarkX, the company’s proprietary bioinformatics platform, couples machine learning with tumor genetics to discover immune evasion pathways that originate in the tumor and enrich clinical strategies for potential responders to its therapies across multiple types of cancer. Larkspur’s founders include Lewis C. Cantley, PhD, professor of medicine at Dana-Farber Cancer Institute, professor of cell biology at Harvard Medical School; Vijay K. Kuchroo, DVM, PhD, professor of neurology at Harvard Medical School, senior scientist at Brigham and Women’s Hospital; and Nathanael Gray, PhD, professor of chemical and systems biology at Stanford University. 1 American Cancer Society. Cancer Facts & Figures 2024. Atlanta: American Cancer Society; 2024. The content above comes from the network. if any infringement, please contact us to modify.

*仅供医学专业人士阅读参考肝脏作为人体重要的代谢器官，负责生成、接收和整合多种信号，以调节全身葡萄糖或脂肪酸等营养物质的供应。与此同时，肝脏也是黑色素瘤、结肠癌、胰腺癌、乳腺癌等多种癌症的主要转移目标地点。与肺部等其它转移部位相比，肝转移与较差预后以及对免疫检查点阻断等癌症疗法的较低响应率相关。因此，了解肝脏独特的微环境和肝转移的复杂分子机制，有助于开发针对肝转移的有效治疗策略。美国哥伦比亚大学的Benjamin Izar等人发表在《自然·癌症》期刊上的最新研究，找到了驱动癌症肝转移的专属基因变异[1]。Pip4k2c是一种激酶的编码基因，研究者们发现，Pip4k2c缺失突变能够帮助肿瘤细胞更加有效地利用胰岛素来促进自身生长，从而特异性地驱动肿瘤细胞向富含胰岛素的肝脏转移。PI3K抑制剂与SGLT2抑制剂或生酮饮食联合治疗，可以在控制胰岛素水平的同时，减少Pip4k2c缺失介导的肝转移。论文截图为找到肝转移的驱动因素，Benjamin Izar等人利用黑色素瘤小鼠模型和体内CRISPR-Cas9筛选等技术，从713种激酶中识别得到激酶PIP4K2C。Pip4k2c基因表达缺失不仅可以增强黑色素瘤肝转移的潜力，而且是“专职掌管”，对肝部位转移具有高度特异性（FDR<0.06）。进一步结合小鼠模型和体外细胞系培养实验，研究者们发现，Pip4k2c的特定结构域缺陷（aa69-75[VMLLPDD→EIFLPNN]）（Pip4k2cAD），会导致肿瘤细胞在胰岛素的刺激下发生PI3K/AKT信号通路被过度激活，提高肿瘤细胞对胰岛素的敏感性，有利于其生长和存活。由于相比于体内其它部位，肝脏大量富集着胰岛素，因此Pip4k2c缺失能够驱动肿瘤细胞依赖于胰岛素梯度特异性地转移至肝脏，而不是肺部，也几乎不影响原发肿瘤的生长。在结直肠癌小鼠模型中可以观察到，Pip4k2c缺失的荷瘤小鼠有75%发生肝转移，远高于携带野生型Pip4k2c的小鼠（20%），肺部转移情况没有增加。另外，Pip4k2c缺失对原发结直肠癌的生长影响较小，证明大幅提高的肝转移率是侵袭能力增强的结果。Pip4k2c缺失促进了肝转移既然Pip4k2c缺失是给PI3K/AKT信号通路的激活拱火，研究者们便想到使用PI3K抑制剂（GDC0941）来使该通路冷静下来，让肿瘤细胞不要对胰岛素这么上头，别一路追到肝脏。结果出乎意料。PI3K抑制剂哪里是雪中送炭，那是雪上加霜啊。研究者们发现，抑制PI3K/AKT信号通路方面，PI3K抑制剂确实做得很好。但另一方面，可能与机体的代谢补偿机制相关，PI3K抑制剂给药竟然会导致荷瘤小鼠肝脏的胰岛素水平升高，加剧肝脏与其它部位的胰岛素水平梯度，反而加重Pip4k2c缺失的荷瘤小鼠肝转移负荷。不过，研究者们很快想到应对之策。他们想到了两种方式，来抵消PI3K抑制剂所引起的肝脏胰岛素水平提高。一种是使用钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂。SGLT2抑制剂作用于肝脏，可以阻止葡萄糖在肝脏中的重新吸收，从而防止胰岛素水平的剧烈波动。另一种是生酮饮食，可以减少肝脏中的糖原储存，有助于改善胰岛素敏感性，降低血糖水平。治疗策略这回成功了。在Pip4k2c缺失的荷瘤小鼠实验中，相比于PI3K抑制剂单独治疗，PI3K抑制剂与SGLT2抑制剂或生酮饮食的联合治疗显著降低肝转移负荷，血糖峰值和血浆C肽水平明显降低。值得注意的是，不管是哪种治疗，携带野生型Pip4k2c或Pip4k2c缺失的小鼠，它们的原位肿瘤生长情况都没有差异。联合治疗效果另外，与小鼠实验结果一致，研究者们对3511例黑色素瘤患者的样本进行分析，发现与患有原发性肿瘤和发生肺转移的患者相比，发生肝转移的患者Pip4k2c表达水平更低，且肿瘤细胞的TCA循环、氧化磷酸化等关键代谢途径强烈富集。很好，这下我们专攻肝转移有了新的方向！参考文献：[1]https://www.nature.com/articles/s43018-023-00704-x本文作者丨张艾迪