XRCC1

After the early wave of immunotherapies proved successful at treating certain cancers, the race has been on to broaden the treatable patient population by fine-tuning specificity and tamping down on toxicities, particularly in solid tumours – and Janux Therapeutics may have just taken the lead for next-generation T-cell engagers. The biotech skyrocketed nearly 230% Tuesday after its two programmes seemed to avoid the severe safety side effects that have hampered the modality’s movement into solid tumours. In a pair of Phase Ia, dose-escalating studies, Janux’s conditional T-cell engagers, called Tumor Activated T Cell Engagers (TRACTrs), did not lead to any cases of high-grade cytokine release syndrome (CRS), “a major toxicity issue that led to discontinuation of multiple T-cell engager clinical candidates,” H.C. Wainwright analysts wrote in a note. “The positive initial data provides validation for the double-masking approach,” they added.Janux’s ‘masking’ technology was developed to ensure tumour-specific activation and avoid on-target toxicities. Both of the clinical TRACTrs comprise a tumour antigen-binding domain and CD3, the latter of which is covered by a peptide mask that can only be removed by tumour-specific proteases. This prevents T-cell binding before the treatment reaches its target, avoiding an overactive immune response. Similarly, TRACTrs also have an albumin binding domain mask to extend half-life, and these can only be removed at the tumour as well.Competitive prostate cancer dataThe first programme, dubbed JANX007, is a PSMA-targeted TRACTr intended to treat advanced or metastatic castration-resistant prostate cancer (mCRPC). So far, 23 patients have received the treatment, and a maximum tolerable dose has yet to be reached. Janux said reported incidents of CRS were “temporary and mild,” with no events higher than Grade 2.At the ≥0.1mg starting dose, 10 of 18 (56%) patients saw a PSA reduction from baseline of at least half, and the next dose level of  ≥0.2mg led to the same PSA reduction in 5 of 6 (83%) evaluable patients. The H.C. Wainwright analysts suggested these results compare favourably with Pluvicto (lutetium Lu 177 vipivotide tetraxetan), a PSMA-targeting radiotherapeutic from Novartis, which was approved by the FDA after demonstrating that 177 of 385 (46%) mCRPC patients experienced a PSA reduction of  50% or more. Janux plans on sharing updated dose expansion data next half.Lung cancer responds Janux’s second candidate is solid tumour-agnostic. JANX008 targets EGFR and is being studied in patients with advanced or metastatic cancers including colorectal cancer, squamous cell carcinoma of the head and neck, non-small-cell lung cancer (NSCLC), and renal cell carcinoma (RCC).Of the 11 treated patients, only two experienced CRS, and both cases were classified as Grade 1. One patient with NSCLC who received a once-weekly 0.15mg dose of JANX008 had a confirmed partial response (PR), with 100% reduction of their lung lesion, elimination of liver metastasis, and no CRS. The PR was maintained through their week-18 scan. Additionally, one patient experienced a 12% reduction of their RCC mass. The company said it is continuing the dose escalation and optimisation of JANX008.

NEW YORK, Aug. 9, 2023 /PRNewswire/ -- The DeGregorio Family Foundation with the support of the Price Family Foundation and the Esophageal Cancer Awareness Association has awarded $87,500 to Dawit Kidane-Mulat, PhD, Associate Professor at Howard University College of Medicine to complete his grant. Dr. Kidane-Mulat is working to enhance the effectiveness of immunotherapy in gastric cancers, which now has a very low success rate, in the five percent range. Continue Reading Dr. Dawit Kidane-Mulat The overarching goal of this study is to harness XRCC1-deficient gastroesophageal cancer cells that will likely enhance the efficacy of immunotherapy response. Dr. Kidane-Mulat is examining how defective XRCC1 and targeting DNA damage response contributes to aberrant innate immune cells inflammatory response. He and his lab are pursuing how inhibition of ATM activity in XRCC1 deficient/low expressing gastric cells induces DNA sensor cGAS/STING mediated aberrant inflammatory response. This work lays the foundation for additional in-depth preclinical studies, and for the development of novel therapeutic strategies for stomach cancer. Commenting on his award, Dr. Kidane-Mulat said, "I am grateful to the DeGregorio Family Foundation. As a result of this award, I am generating a long line of research into understanding the basis of DNA repair/response and immunotherapy treatment in stomach cancer. This grant award is opening a new opportunity to propel the field forward and build a solid foundation for future immunotherapy therapeutic strategies in gastric cancer." In 2020, gastric and esophageal cancers combined to kill over 1.3 million people worldwide— making it the second-leading cause of cancer-related deaths. Patients continue to face poor prognoses following gastric and esophageal cancer diagnoses due to their chemo-resistant behavior and ability to metastasize. "Dr. Kidane-Mulat's grant could be paradigm-changing," concluded Lynn DeGregorio, President and Founder. "We're honored to fund deserving research like this that has the potential to significantly improve how we treat gastroesophageal cancers." The DeGregorio Family Foundation, founded in 2006 after a 10th member of the DeGregorio family died of stomach cancer, has raised more than $8 million to fund innovative research focused on curing gastric and esophageal cancers. It is the only foundation funding research grants for both of these cancers. SOURCE DeGregorio Family Foundation

该研究揭示了去泛素化酶USP15可通过直接去泛素化PARP1以增强其蛋白稳定性，进而导致PARP1的过量表达及BER效率的提升，最终促进肿瘤细胞存活。 世界卫生组织发布的数据显示：近年来乳腺癌发病率逐渐升高，2020年乳腺癌首次超越肺癌，成为全球发病率最高的癌症。2022年，乳腺癌全球发病率高达12.5%，约每八个女性中就会出现一个乳腺癌患者。而在我国，乳腺癌也是女性中发病排名首位的恶性肿瘤，每年约有42万例新增乳腺癌病例，其致死率亦居于前列。 在乳腺癌不同亚型中，三阴性乳腺癌（TNBC）有着转移率高、预后差、患者生存率低等特征，使TNBC成为最凶险的乳腺癌亚型。然而，当前靶向TNBC的有效治疗手段十分匮乏，因此开发TNBC的新型靶向疗法迫在眉睫。三阴性乳腺癌（TNBC）因缺乏雌激素受体（ER）、孕激素受体（PR）及人表皮生长因子受体2（HER2）这三种常见治疗靶标而得名。 肿瘤的发生与发展伴随着DNA修复能力的动态变化。大量研究显示DNA修复的缺陷会导致突变积累，进而引发原癌基因激活、抑癌基因失活，最终介导肿瘤发生；然而，肿瘤在旺盛增殖过程中又面临着复制压力及代谢产生的活性氧等对基因组稳定性造成的巨大威胁，极大程度上依赖于DNA修复机制的活跃运转以维持细胞存活。与此一致，多项研究亦证实某些DNA修复通路在肿瘤细胞中被过度激活。 Poly(ADP-ribose) polymerase 1（PARP1）是多聚ADP-核糖基转移酶家族的重要成员。作为DNA损伤修复中的先锋因子，PARP1被报道在损伤发生后的极短时间内就会被招募至损伤位点，通过多聚ADP-核糖基化XRCC1调控碱基切除修复（BER）。除此之外，它还被报道参与调控DNA双链断裂修复（DSBR）和核苷酸切除修复（NER）。PARP1是肿瘤治疗领域的明星分子，PARP抑制剂（PARPi）已被广泛运用于治疗多种肿瘤，尤其在BRCA1/2缺失的乳腺癌、卵巢癌等肿瘤的临床治疗中显示出卓越的疗效。其中，PARP抑制剂奥拉帕利（Olaparib）已于2018年被批准用于TNBC的临床治疗，但如何扩大奥拉帕利的适用范围并进一步优化其治疗方案以使更多的患者受益仍是当前的重要课题。 此外，2017年在《新英格兰医学杂志》（NEJM）上发表的关于奥拉帕利的三期临床实验数据显示：TNBC患者对奥拉帕利的敏感性高于非三阴性乳腺癌（Non-TNBC）患者，但其中机制尚不明确。因此，解析TNBC及Non-TNBC中PARP1的差异性调控机制将为今后进一步扩大奥拉帕利的适用范围、优化其治疗策略，最终使更广阔的患者群体受益奠定理论基础。 2023年4月3日，同济大学附属第一妇婴保健院、生命科学与技术学院毛志勇教授研究团队在 Nature Cancer 期刊发表了题为：Loss of the receptors ER, PR and HER2 promotes USP15-dependent stabilization of PARP1 in triple-negative breast cancer 的研究论文。 该研究揭示了去泛素化酶USP15可通过直接去泛素化PARP1以增强其蛋白稳定性，进而导致PARP1的过量表达及BER效率的提升，最终促进肿瘤细胞存活。有趣的是，该项工作还首次阐明了在TNBC中雌激素受体（ER）、孕激素受体（PR）及人表皮生长因子受体2（HER2）的表达缺失介导PARP1异常高表达的分子机制，加深了领域内学者对TNBC中基因组稳定性的特异性调控机制的理解，也为未来开发基于PARPi的TNBC特异性治疗方案提供新的机遇。 在该项工作中，团队成员首先通过去泛素化酶文库筛选发现USP15能够与PARP1发生蛋白间相互作用。进一步研究提示USP15可直接与PARP1互作并去泛素化PARP1，从而增强PARP1的蛋白稳定性，进而促进BER修复及基因组稳定性，最终有利于肿瘤细胞生长。这些发现提示USP15将成为肿瘤治疗的新的突破口。 团队成员的进一步发研究发现：与Non-TNBC相比，PARP1在TNBC中的过量表达尤为明显。为理解USP15-PARP1轴是否在TNBC中受到了特异性的调控，团队成员进一步探索了ER、PR及HER2对USP15-PARP1轴的潜在调控作用。深入的机制研究显示：ER可抑制USP15转录，PR可抑制USP15去泛素化酶酶活，而HER2则可通过干扰USP15与PARP1之间的相互作用从而干扰USP15-PARP1信号轴，最终导致细胞对于奥拉帕利的敏感性降低。这一发现既阐释了TNBC患者对奥拉帕利更敏感的分子机制，又为未来进一步优化奥拉帕利的治疗方案、扩大其的适用范围奠定了理论基础。 毛志勇团队长期围绕PARP1与DNA修复的调控机制开展系统性的研究工作，前期工作揭示了SIRT6激活PARP1（Science，2011；PNAS，2012）、cGAS抑制PARP1-timeless互作（Nature，2018）、PARP1-SIRT1-BRG1（Nucleic Acids Research, 2019）及PARP1-ALC1（PNAS, 2020）信号轴调控双链断裂修复的分子机制，而本研究是团队对PARP1调控网络的进一步丰富。 毛志勇教授与蒋颖副教授为本文的共同通讯作者。毛志勇教授团队的博士研究生孙小翔为本文的第一作者。本文的作者还包括唐欢胤博士、陈御助理研究员、博士研究生陈芷茜、胡之易、硕士研究生崔震以及陶雅明硕士。