PIM3

细胞周期蛋白依赖性激酶(CDK)家族在调节细胞周期进程(如CDK1/2/4/6)和RNA转录(如CDK7/8/9/11)中起着不可或缺的作用。 细胞周期蛋白依赖性激酶(CDK)家族在调节细胞周期进程(如CDK1/2/4/6)和RNA转录(如CDK7/8/9/11)中起着不可或缺的作用。由于染色体区域或基因扩增易位而导致的CDKs表达失调与肿瘤的发生有关，使CDKs成为有吸引力的治疗靶点。 PAN-CDK抑制剂(例如，地奈西利和黄烷醇)的开发已经停滞不前，部分原因是治疗指数太窄。与此同时，越来越多的证据表明，CDK9，一种转录CDK，是高周转率癌基因的关键驱动因素，特别是在依赖MYC的癌症中。 图片来源：https://doi-org.libproxy1.nus.edu.sg/10.1186/s12943-023-01762-6 近日，来自美国希望之城国家医疗中心的研究者们在Molecular Cancer杂志上发表了题为“CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma”的文章，该研究揭示了CDK9i诱导表观遗传格局的重新编程，并且超级增强子驱动的选择癌基因的恢复可能有助于对CDK9i的抗性。PIM和PI3K是在DLBCL的异质性环境中规避对CDK9i耐药的潜在靶点。 弥漫性大B细胞淋巴瘤(DLBCL)表现出明显的遗传异质性，导致耐药，迫切需要开发新的治疗方法。细胞周期蛋白依赖性激酶(CDK)的药物抑制剂在DLBCL中显示出临床前的活性，但许多药物在临床开发中停滞不前。 在本研究中，研究者发现CDK9的选择性抑制剂AZD4573抑制了DLBCL细胞的生长。CDK9抑制(CDK9i)导致转录组和蛋白质组的快速变化，多种癌蛋白(如MYC、Mcl-1、JunB、PIM3)的下调，以及磷酸肌苷-3激酶(PI3K)和衰老途径的解除调节。 在RNAPII暂停导致的最初转录抑制之后，研究者观察到包括MYC和PIM3在内的几个癌基因的转录恢复。ATAC-Seq和CHIP-Seq实验表明，CDK9i通过染色质可及性的双向改变诱导表观遗传重塑，抑制启动子的激活，并导致超级增强子景观的持续重新编程。CRISPR文库筛选表明，介体复合体中的SE相关基因以及AKT1对CDK9i具有抗性。 与此一致的是，sgRNA介导的MED12基因敲除使细胞对CDK9i敏感。根据机制发现，研究者将AZD4573与PIM激酶或PI3K抑制剂联合使用。这两种药物在体外均能抑制DLBCL和原代淋巴瘤细胞的增殖和诱导其凋亡，并能延缓DLBCL体内移植小鼠的肿瘤进展和延长其存活时间。 CDK9抑制对启动子和增强子格局的重新编程 图片来源：https://doi-org.libproxy1.nus.edu.sg/10.1186/s12943-023-01762-6 研究者发现，CDK9抑制(CDK9i)迅速耗尽淋巴细胞中的癌基因，随后不可避免地在转录水平上恢复。CDK9i诱导表观遗传重塑，并重新编程超级增强子景观。对CDK9i的耐药性可以通过破坏超级增强子相关蛋白(BRD4，中介复合体)或靶向PIM和PI3K/ATK通路来规避。本研究的发现对这类药物的临床开发具有一定的指导意义。（生物谷 Bioon.com） 参考文献 Elana Thieme et al. CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma. Mol Cancer. 2023 Mar 30;22(1):64. doi: 10.1186/s12943-023-01762-6.

MARCO ISLAND, Fla., Feb. 22, 2023 /PRNewswire/ -- In the fight against cancer, the next step could be evolutionary. Impact BioMedical and its research partner Global Research and Discovery Group today announced that they have finished the first phase of a groundbreaking project that could give humans the edge over cancer. The BNE-1 Antibody Project is the next evolutionary step of cancer research, seeking to develop cancer-suppressing antibodies that would give the human body the ability to not only fight against most cancers, but win. Impact BioMedical and GRDG researchers said that they had successfully completed cloning three new antibody libraries and will now move ahead to advanced "tumor-killing assays" to determine the scope of efficacy against most of the cancers that are available for analysis. "I am very pleased that we now have the antibodies successfully cloned, stable in stasis and look forward to beginning the second phase of this work," said Daryl Thompson, Director of Scientific Initiatives at Global Research and Discovery Group. "As we progress, this research will give us new insights on not only the ways of fighting cancer, but also how the human body can respond and thrive in the face of threats." The BNE-1 Antibody Project got its genesis in a previous cancer-fighting effort, the CRST-1 Project. The earlier research focused on developing a natural, cancer-fighting drug, which inspired by a friendship between Thompson and Marco Island native Christy Bastian. Thompson met Christy Bastian in August 2020 through a mutual friend and the two sparked a friendship. When they met, Bastian was in her second cancer battle. She had fought breast cancer into remission in 2012, but was stricken with a rare and aggressive cancer in 2020 when she met Thompson. Despite her decade-long cancer battles, she had maintained a positive attitude, but the fight had taken its toll, she told Thompson. Her resolve to fight struck a chord with Thompson, who reasoned that instead of focusing on a person's will to fight, why not focus on cutting cancer's ability to attack. "I was literally sitting there listening to someone tell their story about how they're dealing with cancer, and I realized that it's not how hard you punch, but maybe it's more just a will to fight?" said Thompson. "If her will to fight is working for her survival, what if we could take that away cancer's 'will to fight', its tenacity. That's Pim." Pim (proviral integration site for moloney murine leukemia virus) according to the National Institutes of Health, plays a key role in the expression or activation of several cancers. According to Thompson, PIM is what stimulates a cancer cell's ability to fight against drugs that are designed to kill it. Shutting down PIM will shut down cancer's ability to live. That work led to the identification of the molecule that assists in inhibiting Pim, CRST-1 — named after Christy Bastian. "When Daryl told me about the concept of the CRST-1, and how he came to that name, I was honored," said Bastian. "To be affiliated with the initial research and to now to see how this next evolutionary phase develops gives me hope that one day cancer will be a thing of the past." CRST-1 is a non-toxic treatment that has no side effects. It is designed to accompany traditional cancer treatments to increase the effectiveness of the drugs used. It was shown to inhibit PIM 1 and PIM 3 respectively in cell phosphorylation assays. "The CRST-1 project yielded an important drug discovery," said Thompson. "The current BNE-1 project is the next step from CRST-1, to develop cancer-suppressing antibodies." And as with the CRST-1 Project, which is named after Christy, the BNE-1 Project is named in honor of a friend's wife who passed from cancer, Bonnie. "This research is personal for me, and the development of these new strategies should be personal for anyone who knows or has known someone who has fought this disease," said Thompson. The impact of this research could also have a global impact, according to Roscoe Moore, GRDG Chief Scientific Advisor Dr. Roscoe M. Moore, Jr., the retired United States Assistant Surgeon General and former Epidemic Intelligence Services (EIS) Officer at the U.S. Centers for Disease Control. "This line of research represented in BNE-1 Project is important because it is based in naturally-occurring phenomena and, as such, is easier to replicate around the world, especially in places where advanced medical cancers therapies are not readily available," said Moore. The announcement of a successful end of the first phase of research is relevant as it comes on the edge of the Marco Island "Imagination Ball" held later this month at the JW Marriot as a fundraiser for the American Cancer Society. The CRST-1 project — and Christy Bastian's story — was first revealed at the Imagination Ball several years ago at the Project's inception. "I am especially fond of the Imagination Ball, as I have always considered Marco Island and the Everglades home," said GRDG's Thompson. "I view this current BNE-1 project and as one of our most challenging but important projects in part because it was inspired and conceptualized at Marco Island, which I find endearing." About Impact BioMedical, Inc. Impact BioMedical, Inc. ("Impact BioMedical") is a wholly owned subsidiary of DSS. Impact BioMedical strives to leverage its scientific know-how and intellectual property rights to provide solutions that have been plaguing the biomedical field for decades. By tapping into the scientific expertise of GRDG Sciences, LLC, Impact BioMedical pledges to undertake a concerted effort in the R&D, drug discovery and development for the prevention, inhibition, and treatment of neurological, oncological and immuno -related diseases. For more information on Impact BioMedical visit . Media Contact: Don Manley 239-206-6920 354233@email4pr.com

PIM激酶(Moloney白血病病毒的前病毒整合位点)是一个丝氨酸/苏氨酸蛋白激酶家族，在细胞发育、免疫调节和肿瘤发生中发挥作用。对原始Pim-1的早期研究导致发现Pim-1家族在淋巴瘤中的致癌作用。 PIM激酶(Moloney白血病病毒的前病毒整合位点)是一个丝氨酸/苏氨酸蛋白激酶家族，在细胞发育、免疫调节和肿瘤发生中发挥作用。对原始Pim-1的早期研究导致发现Pim-1家族在淋巴瘤中的致癌作用。 尽管Pim-2与Pim-1只有55%的氨基酸同源性，但它被认为是Pim-1的补偿蛋白，因为它有非常相似的激酶域。该家族的第三个成员，pim-3，被发现催化组蛋白磷酸化和自磷酸化。这三种Pim蛋白都可以磷酸化丝氨酸和苏氨酸氨基酸，并且可以激活相似的细胞通路。这使得研究人员相信，单个Pim激酶是代偿性的，因此一个Pim激酶的丢失可以通过表达另一个Pim激酶来缓解。 原文链接: https://doi-org.libproxy1.nus.edu.sg/10.1186/s12943-023-01721-1 近日，来自堪萨斯大学医学中心的研究者们在Molecular Cancer杂志上发表了题为“Targeting Pim kinases in hematological cancers: molecular and clinical review”的综述性文章，该研究总结了靶向Pim激酶在血液系统肿瘤中的分子和临床研究进展 几十年的研究已经认识到Pim激酶在淋巴增生性疾病中的坚实作用。在JAK/STAT和酪氨酸激酶受体信号转导之后，Pim激酶经常上调，调节细胞的增殖、存活、代谢、细胞转运和信号转导。 靶向Pim激酶是一种有趣的方法，因为Pim激酶的敲除会导致体内的非致命性表型，这表明临床抑制Pim可能有较少的副作用。此外，ATP结合位点提供了独特的特性，可用于开发针对一种或所有Pim异构体的小分子抑制剂。 这篇综述对Pim激酶的表达及其与血液癌的关系进行了进一步的研究。对目前和过去的临床试验和Pim激酶抑制剂的体外特性进行了综述，并讨论了未来的发展方向。目前的研究表明，当与多种药物靶向治疗相结合时，Pim激酶抑制可能是最有价值的。 骨髓增殖性肿瘤中Pim激酶活性升高的细胞机制 原文链接: https://doi-org.libproxy1.nus.edu.sg/10.1186/s12943-023-01721-1 使用第一代Pim抑制剂的临床试验未能显著减轻患者的疾病负担或减轻化疗耐药性。此外，较高剂量的Pim抑制剂可能会产生非靶点效应，并可能导致不良反应，包括心脏事件、胃肠道问题、发热性中性粒细胞减少症和皮疹等。 较新的、高度特异的Pim激酶抑制剂，如PIM447、UZANSERTIB和TP-3654可以克服这些问题，允许PIM在较低浓度下靶向。另一种选择是通过单抗Pim抗体治疗或间接靶向Pim激酶调节因子来直接靶向Pim激酶。在一些白血病细胞的细胞表面发现了Pim-1，这种细胞可以被单抗Pim-1(mPim-1)靶向治疗而失去增殖。 未来的研究仍然需要委派单独的Pim亚型的特定作用，它们的下游靶点，以及如何调节Pim以更精确地改进治疗方案。然而，大量使用Pim抑制剂进行的临床前和临床试验表明，在淋巴增生性疾病和实体瘤中靶向Pim途径具有临床意义。（生物谷 Bioon.com） 参考文献 Marcia Bellon et. Targeting Pim kinases in hematological cancers: molecular and clinical review. Mol Cancer. 2023 Jan 25;22(1):18. doi: 10.1186/s12943-023-01721-1.