Anophthalmia With Pulmonary Hypoplasia

进一步整合多组学发现，GLUT1/ALDOB/G6PD代谢轴在Glucomet-PDAC代谢重编程过程中发挥重要作用。首先，在Glucomet-PDAC中，Glut1高表达，转运更多的葡萄糖进入肿瘤细 研究团队以28例胰腺癌类器官为模型，系统性收集了代谢组学、全基因组学、转录组学、染色质开放性以及药物敏感性信息。利用代谢组学对PDAC进行分型，鉴定了2种代谢亚型，分别富集糖代谢（Glucomet-PDAC）和脂代谢（Lipomet-PDAC）。与Lipomet-PDAC相比，Glucomet-PDAC对化疗更抵抗，同时具有Glucomet-PDAC特征的病人预后更差。 进一步整合多组学发现，GLUT1/ALDOB/G6PD代谢轴在Glucomet-PDAC代谢重编程过程中发挥重要作用。首先，在Glucomet-PDAC中，Glut1高表达，转运更多的葡萄糖进入肿瘤细胞。其次，ALDOB表达的降低释放了G6PD的活性，提高了氧化型戊糖磷酸途径的代谢通量。氧化型戊糖磷酸途径代谢通量的增加在Glucomet-PDAC中合成了更多参与DNA合成原料，诱导了其对化疗药物的耐药性。在Glucomet-PDAC中敲低GLUT1、过表达ALDOB或者敲低G6PD都可以导致细胞对化疗药物敏感性的增加。同样，GLUT1和G6PD的抑制剂在体内外都可增加PDAC对化疗药物的敏感性。 最后，通过虚拟筛选及体内外验证，发现Aurora的两个临床抑制剂MLN8054及Alisertib可以有效抑制G6PD的活性并增加化疗药物的敏感性。该研究揭示了与PDAC化疗敏感性相关的潜在代谢异质性，并通过化疗和GLUT1/ALDOB/G6PD轴抑制剂的组合为化疗耐药性glucomet-PDAC患者开发了一种有希望的药理学策略。 胰腺癌代谢分型及其重编程诱导的耐药模式图

代谢重编程被认为是一种新的化疗耐药机制，但胰腺导管腺癌(PADCs)的代谢特征仍不清楚。2023年8月18日，海军军医大学金钢、中国科学院分子细胞科学卓越创新中心高栋、陈洛南、杨巍维及中国科学院上海营养与健康研究所尹慧勇共同通讯在Cell Reports Medicine 在线发表题为“Metabolic classification suggests the GLUT1/ALDOB/G6PD axis as a therapeutic target in chemotherapy-resistant pancreatic cancer”的研究论文，该研究描述了PDAC类器官的代谢组学特征，并将它们分为glucomet-PDAC(高糖代谢水平)和lipomet-PDAC(高脂代谢水平)。glucomet-PDACs比lipomet-PDACs对化疗的抵抗力更强，葡萄糖醛PDAC患者的预后更差。综合分析表明，GLUT1/醛缩酶B（ALDOB）/葡萄糖-6-磷酸脱氢酶（G6PD）轴通过重塑葡萄糖代谢诱导化疗耐药性。在具有高GLUT6和低ALDOB表达的glucomet-PDAC中鉴定出糖酵解通量增加，G1PD活性和嘧啶生物合成增加，这些表型可以通过抑制GLUT1表达或增加ALDOB表达来逆转。GLUT1或G6PD的药理学抑制增强了glucomet-PDAC的化疗反应。该研究揭示了与PDAC化疗敏感性差异相关的潜在代谢异质性，并通过化疗和GLUT1 / ALDOB / G6PD轴抑制剂的组合为化疗耐药性glucomet-PDAC患者开发了一种有希望的药理学策略。胰腺导管腺癌(PDAC)是最致命的恶性肿瘤之一，其5年生存率为11%。化疗可显著延长PDAC患者的生存期，但由于耐药机制复杂且不明确，PDAC患者的化疗有效率仍然较低。尽管许多研究都集中在基于基因组和转录组特征的PDAC分类上，但目前定义的PDAC特征并不能指示化疗敏感性或指导治疗决策。代谢重编程被认为是一种新兴的治疗耐药机制，并为癌症治疗提供了机会。然而，由于大量基质细胞的存在，很少有研究检测PDAC的代谢失调和异质性，这使得获取精确的肿瘤特异性代谢物信息变得困难。因此，系统地表征PDAC的代谢和基因组图谱可能揭示化疗敏感性的潜在分子细节，并促进靶向治疗的发展，以预防或逆转化疗耐药。由于代谢改变是癌症的标志之一，因此人们对代谢（特别是葡萄糖代谢）与PDAC启动，进展和治疗耐药性之间的关系越来越感兴趣。先前的研究已经在糖酵解、脂肪生成和氧化还原途径中具有不同代谢物水平的PDAC细胞系中进行，这些细胞系对多种代谢抑制剂表现出明显的敏感性。此外，个体PDAC肿瘤内的代谢异质性已被确定有助于OXPHOS抑制剂的治疗耐药在小鼠模型中，KRAS突变和缺氧是已知的PDAC糖酵解途径的诱导剂。在小鼠模型中，通过条件性失活Nsdhl或他汀类药物治疗破坏远端胆固醇生物合成可将经典表型转换为基础表型。根据糖酵解和胆固醇生成基因的中位标准化表达，鉴定出四种代谢表达亚型，糖酵解肿瘤的中位生存期最短。这些研究强调了表征代谢特征和确定PDAC细胞存活和化疗耐药的基本途径的必要性，这可能提供一个治疗窗口。机理模式图（图源自Cell Reports Medicine）患者来源的癌症类器官已经成为一种研究模型，并且在再现原发肿瘤的特征方面已被证明优于传统细胞系。该研究建立了一个大型的PDAC类器官生物库，并通过多组学整合分析对这些类器官进行了表征。在这里，作者表征了PDAC类器官的代谢特征，并确定了两种代谢亚型，称为glucomet-PDAC(高糖代谢)和lipomet-PDAC(高脂代谢)。作者发现GLUT1/醛缩酶B (ALDOB)/葡萄糖-6-磷酸脱氢酶(G6PD)轴调节葡萄糖代谢重编程并赋予glucomet-PDAC化疗耐药。此外，该研究提出了一种潜在的药理学策略，包括靶向GLUT1/ALDOB/G6PD轴，以增强glucomet-PDAC的治疗敏感性。文章来源“iNture”责编|文竞择校对|文竞择End往期精选围观历史性突破！不需卵子和精子就可以合成人类胚胎热文富豪用儿子血浆“回春”科学吗？Science：血液牛磺酸缺乏驱动衰老热文世界首例！35岁的她，通过机器人操刀移植的子宫，成功诞下宝宝热文为了避免心脏骤停，53岁的他成为“第一个”植入开创性除颤器的心脏病患者热文首次披露！175家生物制药公司的薪资数据：薪资中位数达20万美元点击“阅读原文”，了解更多~

CARLSBAD, Calif., Aug. 17, 2023 (GLOBE NEWSWIRE) -- Qualigen Therapeutics, Inc. (Nasdaq: QLGN), a clinical-stage therapeutics company focused on developing treatments for adult and pediatric cancers with potential for Orphan Drug Designation, announced today it is partnering with Translational Drug Development (TD2) as the contract research organization (CRO) to conduct the Phase 1 clinical development of lead drug candidate QN-302. Qualigen received US FDA IND clearance earlier this month to initiate a Phase 1 clinical trial of QN-302, a small molecule G-Quadruplex (G4)-selective transcription inhibitor, for the treatment of advanced or metastatic solid tumors. Tariq Arshad, M.D., M.B.A., Chief Medical Officer, stated: “I am delighted that the FDA has cleared QN-302 to enter the clinic for the proposed Phase 1 clinical trial in patients with advanced or metastatic patients with solid tumors. This furthers our ongoing investigation of a potentially exciting new therapeutic approach for this group of cancer patients with high unmet medical need along with our assessment of corresponding biomarkers relevant to G4 expression. TD2, our CRO partner, has been instrumental in bringing us to this point. Their demonstrated ability to meet critical timelines within budget reinforces its status as an industry leader in preclinical and clinical oncology drug development, maximizing the opportunity for QN-302 to reach the patients who need it the most.” TD2 is a precision oncology drug development organization integrating preclinical, clinical, and regulatory expertise and providing expert drug development services, including the design and execution of oncology clinical trials. TD2 has a proven track record of obtaining IND clearances and managing complex trial designs, including recruitment for Orphan diseases, to accomplish first patient dosing as quickly as possible. “The successful IND filing of QN-302 is the result of a strong partnership and shared dedication between Qualigen and TD2 to advance cancer therapeutics into patients who may have run out of options," said Stephen Gately, Ph.D., President and CEO of TD2. "We appreciate the chance to work with Qualigen on this exciting development program and look forward to the upcoming clinical data.” Qualigen Therapeutics secured exclusive worldwide rights to QN-302 in January 2022 from University College London (UCL). QN-302 was invented and developed by Professor Stephen Neidle and his team from the UCL School of Pharmacy, one of the top ten pharmacy and pharmacology research institutions in the world. Professor Neidle has a distinguished 30+ year history in nucleic acid research and drug design with over 500 published papers and 14 patents and has been a member of Qualigen’s QN-302 Scientific Advisory Board since February 2022. Professor Neidle stated, “I’m delighted that our novel experimental drug QN-302 is at this very exciting stage of now having FDA clearance for clinical evaluation. We are so pleased that Qualigen has not only shared our vision but has taken QN-302 with remarkable skill and speed to this important milestone. I am proud that we have long been a pioneer of the quadruplex targeting concept and now look forward to the clinical development of QN-302.” Qualigen plans to initiate activation of the first Phase 1 clinical trial site and enroll the first patient in the Phase 1 dose escalation clinical study later this year. Qualigen will enroll patients with advanced or metastatic solid tumors who have failed prior therapy. About QN-302 QN-302 is a small molecule G-Quadruplex (G4)-selective transcription inhibitor in Phase 1 clinical development for the treatment of G4-expressing solid tumors, such as pancreatic cancer (PDAC), prostate cancer, sarcomas, and others. QN-302 stabilizes G4 complexes prevalent in the promoter region of oncogenes in many tumor types, impeding transcription of G4-containing cancer genes and may potentially offer a tumor-agnostic clinical approach to treatment. Orphan Drug Designation (ODD) was granted by the FDA in January of this year for QN-302 for the intended indication of pancreatic cancer. About Qualigen Therapeutics, Inc. Qualigen Therapeutics, Inc. is a clinical-stage therapeutics company focused on developing treatments for adult and pediatric cancer. Our investigational QN-302 compound is a small molecule selective transcription inhibitor with strong binding affinity to G4s prevalent in cancer cells; such binding could, by stabilizing the G4s against “unwinding,” help inhibit cancer cell proliferation. The investigational compounds within Qualigen’s family of Pan-RAS oncogene protein-protein interaction inhibitor small molecules are believed to inhibit or block the binding of mutated RAS genes’ proteins to their effector proteins, thereby leaving the proteins from the mutated RAS unable to cause further harm. In theory, such mechanism of action may be effective in the treatment of about one quarter of all cancers, including certain forms of pancreatic, colorectal, and lung cancers. About Translational Drug Development (TD2) TD2 is a leader in precision oncology, providing innovative services for improved drug development. Using a dedicated, expert team with broad experience and understanding in cancer medicine, TD2 is uniquely positioned to support accelerated development of novel therapeutics. Rigorous and high-throughput translational preclinical development services, combined with regulatory affairs expertise, enables customized clinical trial design and execution. Our broad suite of capabilities encourages the timely selection of patient populations who are most likely to benefit from a new agent, and the rapid identification of clinically significant endpoints. TD2 is committed to reducing the risks and uncertainty inherent in the drug development process with the ultimate goal of accelerating patient access to promising treatments. For more information, visit www.TD2inc.com. Forward-Looking Statements This news release contains forward-looking statements by Qualigen that involve risks and uncertainties and reflect the Company's judgment as of the date of this release. These statements include those related to the Company's prospects and strategy for development of its therapeutic drug candidates, including the anticipated timeline for initiating the Company’s Phase 1 clinical trial and enrolling and dosing of patients and the identification of a late in vivo candidate. Actual events or results may differ from the Company's expectations. There can be no assurance that the Company will be able to successfully develop any drugs (including QN-302, Pan-RAS and QN-247); that preclinical development of the Company's drugs (including Pan-RAS and QN-247) will be completed on any projected timeline or will be successful; that any clinical trials will be approved to begin by or will proceed as contemplated by any projected timeline, or at all; that any future clinical trial data will be favorable or that such trials will confirm any improvements over other products or lack negative impacts; that any drugs will receive required regulatory approvals (or Fast Track designation or Orphan Drug status) or that they will be commercially successful; that patents will issue on the Company's owned and in-licensed patent applications; that such patents, if any, and the Company's currently owned and in-licensed patents would prevent competition; or that the Company will be able to procure or earn sufficient working capital to complete the development, testing and launch of the Company's prospective therapeutic products (including QN-302, Pan-RAS and QN-247). The Company's stock price could be harmed if any of the events or trends contemplated by the forward-looking statements fail to occur or is delayed or if any actual future event otherwise differs from expectations. Additional information concerning these and other risk factors affecting the Company's business can be found in the Company's prior filings with the Securities and Exchange Commission, including its most recent annual report on Form 10-K, all of which are available at www.sec.gov. The Company disclaims any intent or obligation to update these forward-looking statements beyond the date of this news release, except as required by law. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. For more information about Qualigen Therapeutics, Inc., please visit www.qlgntx.com. Contact:Investor Relations760-530-6487ir@qlgntx.com. Source: Qualigen Therapeutics, Inc.