Rhabdoid Tumor

Scientists reversed an aggressive cancer, reverting malignant cells towards a more normal state. Rhabdoid tumors are an aggressive cancer which is missing a key tumor suppressor protein. Scientists discovered that removing a second protein from cancer cells already experiencing tumor suppressor loss can reverse cancer cell identity. St. Jude Children's Research Hospital scientists reversed an aggressive cancer, reverting malignant cells towards a more normal state. Rhabdoid tumors are an aggressive cancer which is missing a key tumor suppressor protein. Findings showed that with the missing tumor suppressor, deleting or degrading the quality control protein DCAF5 reversed the cancer cell state. These results suggest a new approach to curing cancer -- returning cancerous cells to an earlier, more normal state rather than killing cancer cells with toxic therapies -- may be possible. The results were published today in Nature. "Rather than making a toxic event that kills rhabdoid cancer, we were able to reverse the cancer state by returning the cells toward normal," said senior author Charles W.M. Roberts, MD, PhD, Executive Vice President and St. Jude Comprehensive Cancer Center director. "This approach would be ideal, especially if this paradigm could also be applied to other cancers." "We found a dependency which actually reverses the cancer state," said first author Sandi Radko-Juettner, PhD, a former St. Jude Graduate School of Biomedical Sciences student, now a Research Program Manager for the Hematological Malignancies Program at St. Jude. "Standard cancer therapies work by causing toxicities that also damage healthy cells in the body. Here, it appears that we're instead fixing the problem caused by the loss of a tumor suppressor in this rhabdoid cancer." Drugging the un-targetable In many cancers, there is no easily druggable target. Often, these cancers are caused by a missing tumor suppressor protein, so there is nothing to target directly as the protein is missing. Loss of tumor suppressors is much more common than a protein gaining the ability to drive cancer. Consequently, finding a way to intervene therapeutically in these tumors is a high priority. The researchers were looking for a way to treat an aggressive set of cancers caused by the loss of the tumor suppressor protein SMARCB1 when they found a new approach to treatment. The St. Jude group found a little-studied protein, DCAF5, was essential to rhabdoid tumors missing SMARCB1. Initially, they identified DCAF5 as a target, using the Dependency Map (DepMap) portal, a database of cancer cell lines and the genes critical for their growth. DCAF5 was a top dependency in rhabdoid tumors. After the initial finding, the scientists genetically deleted or chemically degraded DCAF5. The cancer cells reverted to a non-cancerous state, persisting even in a long-term mouse model. "We saw a spectacular response," Roberts said. "The tumors melted away." Removing quality control to reverse cancer Normally, SMARCB1 is an essential component of a larger chromatin-regulating complex of proteins called the SWI/SNF complex. Unexpectedly, the study found that in the absence of SMARCB1, DCAF5 recognizes SWI/SNF as abnormal and destroys the complex. When DCAF5 degrades them, the researchers showed that SWI/SNF re-forms and maintains its ability to open chromatin and regulate gene expression. While the SWI/SNF activity level in the absence of SMARCB1 was to a lesser extent than usual, it was nonetheless sufficient to reverse the cancer state fully. "DCAF5 is doing a quality control check to ensure that these chromatin machines are built well," Roberts said. "Think of a factory assembling a machine. You need quality checks to examine and find faults and to pull it off the line if it doesn't meet standards. DCAF5 is doing such quality assessments for the assembly of SWI/SNF complexes, telling the cell to get rid of complexes if SMARCB1 is absent." "The mutation of SMARCB1 shuts off gene programs that prevent cancer. By targeting DCAF5, we're turning those gene programs back on," Radko-Juettner said. "We're reversing the cancer state because the cell is becoming more 'normal' when these complexes aren't targeted for destruction by DCAF5." Future therapeutic opportunities to reverse cancer "From a therapeutic perspective, our results are fascinating," Radko-Juettner said. "DCAF5 is part of a larger family of DCAF proteins that have been shown to be drug targetable. We showed that when DCAF5 is absent, mice had no discernable health effects, so we could potentially target DCAF5. This can kill the cancer cells but shouldn't affect healthy cells. Targeting DCAF5 thus has the potential to avoid the off-target toxicity of radiation or chemotherapy, making it a promising therapeutic avenue to pursue." Beyond DCAF5, the findings could have implications for other cancers driven by the loss of a tumor suppressor. "We have demonstrated a beautiful proof of principle," Roberts said. "Myriad types of cancers are caused by tumor suppressor loss. We hope we may have opened the door to thinking about new ways to approach targeting at least some of these by reversing, instead of killing, cancer."

LP-184 is the first of Lantern’s drug candidates developed by leveraging Lantern’s AI platform, RADR® US FDA previously granted LP-184 Rare Pediatric Disease Designation and Orphan Drug Designation (ODD) for the treatment of pediatric patients with ATRT DALLAS--(BUSINESS WIRE)-- Lantern Pharma, Inc. (NASDAQ: LTRN), an artificial intelligence (AI) company developing targeted and transformative cancer therapies using its proprietary RADR® AI and machine learning (ML) platform with multiple clinical-stage drug programs, received a notice of allowance from the United States Patent and Trademark Office (USPTO) covering a method of treatment for Atypical Teratoid Rhabdoid Tumor (ATRT) using LP-184, an aggressive and rapidly growing form of cancer of the central nervous system (CNS). “This patent allowance further fortifies Lantern Pharma's intellectual property portfolio, providing us with an additional layer of protection for our potential blockbuster LP-184 program, which is being developed for multiple targeted oncology indications, including ATRT in pediatric patients,” said Panna Sharma, CEO of Lantern Pharma. “Historically, pediatric ATRT has been treated with a combination of surgery, radiation, and chemotherapy, but unfortunately, these approaches have often resulted in unfavorable long-term outcomes for the children affected.” Drs. Kosj and Jaymi Yamoah, Co-founders of Hope4ATRT, a research entity dedicated to directing resources and research to families in the fight against ATRT, commented, “As parents of a child who did not survive ATRT, we are compelled to advocate for more effective and less toxic treatment options for children still in this battle, and we are always thrilled to see progress in ATRT research. The work by Lantern scientists to rapidly develop new therapies with potential to treat ATRT brings us hope for the future.” Sharma continued, “The urgent need for new treatment options for pediatric brain cancers cannot be overstated. Our in-silico and in-vivo observations indicate that LP-184 has the potential to become an essential part of the treatment options for these patients, and this patent allowance provides a further assurance of protection for our advances in the treatment of this devastating disease.” LP-184 is the first of Lantern’s drug candidates developed by leveraging Lantern’s AI and ML platform, RADR®, to advance to a first-in-human Phase 1 basket trial. Lantern has rapidly advanced the clinical development of LP-184, activated the initial clinical trial sites, and has begun screening patients. Indications for the LP-184 trial are anticipated to include relapsed/refractory advanced pancreatic cancer, glioblastoma (GBM), brain metastases (brain mets), and multiple other recurring, advanced solid tumors with DNA damage response deficiencies. The dosage and safety data obtained in the Phase 1 trial will be used to advance the CNS indications, including ATRT, for a future Phase 2 trial to be sponsored by Lantern’s wholly-owned subsidiary, Starlight Therapeutics Inc. Globally, the aggregate annual market potential of LP-184’s target indications is estimated to be approximately $10+ billion, consisting of $5+ billion for CNS cancers and $6+ billion for other solid tumors. The U.S. Food and Drug Administration (FDA) has previously granted LP-184 Rare Pediatric Disease Designation and Orphan Drug Designation (ODD) for the treatment of pediatric patients with ATRT. The FDA has also previously granted LP-184 ODD for the treatment of pancreatic cancer and for the treatment of malignant glioma, including GBM. A notice of allowance is issued after the USPTO determines that the prosecution on the merits of a patent has been completed and grants the patent upon payment of the patent issuance fee. Additional corresponding patent applications are pending in Europe, Japan, Canada, and Australia. About ATRT ATRT is an aggressive and rare form of cancer of the central nervous system that predominantly affects children under the age of three. The National Cancer Institute (NCI) classifies ATRT as Grade IV tumors, meaning they are malignant (cancerous), aggressive, and fast-growing. The root genetic cause of ATRTs is attributed to bi-allelic mutations that inactivate either SMARCB1 (also known as INI1) or SMARCA4. Approximately 90 percent of pediatric ATRTs can be attributed to alterations in the SMARCB1 gene. SMARCB1 was included among several genes whose expression negatively correlated with LP-184 sensitivity in tumors. This in silico correlation was confirmed by in vitro and in vivo assessments of LP-184 in ATRT, with the highest potency of LP-184 in vivo having been seen in ATRT xenografts. About Lantern Pharma: Lantern Pharma (NASDAQ: LTRN) is an AI company transforming the cost, pace, and timeline of oncology drug discovery and development. Our proprietary AI and machine learning (ML) RADR® platform leverages over 34 billion oncology-focused data points and a library of 200+ advanced ML algorithms to help solve billion-dollar, real-world problems in oncology drug development. By harnessing the power of AI and with input from world-class scientific advisors and collaborators, we have accelerated the development of our growing pipeline of therapies including eleven cancer indications and an antibody-drug conjugate (ADC) program. On average, our newly developed drug programs have been advanced from initial AI insights to first-in-human clinical trials in 2-3 years and at approximately $1.0-2.0 million per program. Our lead development programs include two Phase 2 clinical programs and multiple upcoming Phase 1 clinical trials anticipated for 2023. We have also established a wholly-owned subsidiary, Starlight Therapeutics Inc., to focus exclusively on the clinical execution of our promising therapies for CNS and brain cancers, many of which have no effective treatment options. Our AI-driven pipeline of innovative product candidates is estimated to have a combined annual market potential of over $15 billion USD and have the potential to provide life-changing therapies to hundreds of thousands of cancer patients across the world. Please find more information at: Website: LinkedIn: X/Twitter: @lanternpharma Newsletter – The Spark: Sign-up here Forward-looking Statements: This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. These forward-looking statements include, among other things, statements relating to: future events or our future financial performance; the potential advantages of our RADR® platform in identifying drug candidates and patient populations that are likely to respond to a drug candidate; our strategic plans to advance the development of our drug candidates and antibody drug conjugate (ADC) development program; estimates regarding the development timing for our drug candidates and ADC development program; expectations and estimates regarding clinical trial timing and patient enrollment; our research and development efforts of our internal drug discovery programs and the utilization of our RADR® platform to streamline the drug development process; our intention to leverage artificial intelligence, machine learning and biomarker data to streamline and transform the pace, risk and cost of oncology drug discovery and development and to identify patient populations that would likely respond to a drug candidate; estimates regarding patient populations, potential markets and potential market sizes; sales estimates for our drug candidates and our plans to discover and develop drug candidates and to maximize their commercial potential by advancing such drug candidates ourselves or in collaboration with others. Any statements that are not statements of historical fact (including, without limitation, statements that use words such as "anticipate," "believe," "contemplate," "could," "estimate," "expect," "intend," "seek," "may," "might," "plan," "potential," "predict," "project," "target," "model," "objective," "aim," "upcoming," "should," "will," "would," or the negative of these words or other similar expressions) should be considered forward-looking statements. There are a number of important factors that could cause our actual results to differ materially from those indicated by the forward-looking statements, such as (i) the risk that our research and the research of our collaborators may not be successful, (ii) the risk that none of our product candidates has received FDA marketing approval, and we may not be able to successfully initiate, conduct, or conclude clinical testing for or obtain marketing approval for our product candidates, (iii) the risk that no drug product based on our proprietary RADR® AI platform has received FDA marketing approval or otherwise been incorporated into a commercial product, and (iv) those other factors set forth in the Risk Factors section in our Annual Report on Form 10-K for the year ended December 31, 2022, filed with the Securities and Exchange Commission on March 20, 2023. You may access our Annual Report on Form 10-K for the year ended December 31, 2022 under the investor SEC filings tab of our website at or on the SEC's website at . Given these risks and uncertainties, we can give no assurances that our forward-looking statements will prove to be accurate, or that any other results or events projected or contemplated by our forward-looking statements will in fact occur, and we caution investors not to place undue reliance on these statements. All forward-looking statements in this press release represent our judgment as of the date hereof, and, except as otherwise required by law, we disclaim any obligation to update any forward-looking statements to conform the statement to actual results or changes in our expectations.

导读：染色质重塑子SMARCA4/BRG1是一个关键的表观遗传调控因子，在协调脑肿瘤发展的分子程序中发挥多种作用。BRG1在脑癌中的功能在很大程度上是特定于肿瘤类型的，并且在肿瘤亚型之间存在进一步的差异，这突出了其复杂性。SMARCA4表达的改变与髓母细胞瘤、低级别胶质瘤(如少突胶质细胞瘤)、高级别胶质瘤(如胶质母细胞瘤)和非典型/畸胎样横纹肌样肿瘤有关。脑癌中的SMARCA4突变主要发生在关键的催化atp酶结构域，该结构域与肿瘤抑制活性相关。然而，相反地，SMARCA4在没有突变的情况下通过在其他脑肿瘤中的过表达促进肿瘤发生。这篇综述探讨了SMARCA4与各种脑癌类型之间的多方面相互作用，重点介绍了它在肿瘤发病机制中的作用，它调节的途径，以及在理解突变的功能相关性方面取得的进展。我们讨论了靶向SMARCA4的进展，以及将这些进展转化为辅助治疗的潜力，从而增强当前脑癌治疗方法。https://www-nature-com.libproxy1.nus.edu.sg/articles/s41388-023-02773-9研究背景 01 SMARCA4在癌症中的表观遗传调控作用表观遗传调控是影响细胞正常功能的重要基因表达调控机制。表观遗传学是指在不改变DNA序列的情况下调节基因表达的可遗传变化。癌症是一种由信号通路异常活动驱动的疾病，因此表观遗传调控在控制恶性细胞转化过程中发生的功能变化中起着重要作用。癌症中存在一定程度的隐性变异，不能仅用遗传改变来解释，而表观遗传改变可能是原因之一。使癌细胞具有生长优势的驱动突变通常位于表观遗传调节基因中。这与脑癌尤其相关，因为许多脑癌主要发生在儿科患者中，因此缺乏作为衰老自然结果积累的相当数量的乘客突变。atp依赖性染色质重塑是一种重要的表观遗传机制，通过控制染色质的动态和高度组织化状态来调节基因表达。染色质重塑蛋白的表达改变是一种常见的泛癌症主题。开关缺陷/蔗糖不可发酵(SWI/SNF)复合体是一种特征明确的染色质重塑复合体，在大约20%的人类肿瘤中发生突变，这与我们熟悉的肿瘤抑制基因TP53的突变模式相当。哺乳动物SWI/SNF复合物有三类，它们在亚基组成、基因组定位和非冗余功能方面存在差异。这些是典型的BRG1/ brm相关因子(BAF)，多溴化相关因子(PBAF)，以及最近定义的非典型(ncBAF)，由于独特的GLTSCR1亚基，也称为GBAF。所有SWI/SNF复合物都聚集在包含由BAF155/BAF170(基因名称SMARCC1/2)和一个BAF60A/B/C亚基(SMARCD1/2/3)组成的二聚体的初始核心周围，然后结合复合物特异性亚基。atp酶亚基BRG1 (SMARCA4)或BRM (SMARCA2)结合到核心BAF模块并招募辅助亚基以完成SWI/SNF复合物的形成。在人类癌症中，SWI/SNF复合体最常发生突变的亚基之一是SMARCA4，它编码BRG1蛋白。BRG1利用ATP水解产生的能量对核小体进行物理重排，改变染色质的可及性，使BRG1成为协调癌症基因表达程序的核心组成部分。SWI/SNF染色质重塑复合体调节基因表达除了转录外，BRG1还在DNA过程中发挥作用，这进一步促进了其在癌症中的重要性。研究表明，BRG1通过核小体重定位和修复因子的募集促进双链断裂处的DNA修复，而BRG1缺失则会诱导复制应激，这是基因组不稳定的主要原因。BRG1与癌症之间的关联以及观察到的遗传改变类型高度依赖于癌症类型。多项泛癌症研究已经从人类肿瘤测序数据中记录了SMARCA4基因的改变，并观察到各种各样的畸变。BRG1通常被描述为在肺癌、卵巢癌、皮肤癌和淋巴瘤等癌症中具有肿瘤抑制作用。相反，BRG1参与协调和维持促进白血病、乳腺癌和前列腺癌等其他类型癌症发生的关键信号通路。在脑癌中，BRG1同时具有抑瘤和致癌功能。虽然有充分的文献证明SMARCA4在癌症中经常发生突变，但对特定SMARCA4突变对细胞生理学的功能后果知之甚少，并且在临床环境中缺乏有用的应用。这篇综述讨论了目前对BRG1在脑癌中所起作用的理解以及脑癌类型之间存在的差异。我们概述了SMARCA4临床突变的现有知识，突变的功能后果，以及针对SMARCA4作为潜在治疗策略的最新进展。SMARCA4在脑癌中的作用中枢神经系统(CNS)肿瘤是世界范围内癌症死亡的主要原因，其中绝大多数中枢神经系统肿瘤发生在脑部。中枢神经系统肿瘤是婴幼儿最常见的实体瘤。与其他类型的癌症相比，脑癌相关癌症死亡的死亡率和寿命损失要大得多，因为治疗选择有限，而且严重的副作用可能会损害生活质量。SMARCA4是多种类型脑癌(包括髓母细胞瘤、胶质瘤和非典型畸胎瘤/横纹肌样肿瘤)中反复突变的基因。SMARCA4在肿瘤发生中的作用是高度可变的，很大程度上取决于脑肿瘤的类型，而SMARCA4在脑肿瘤中的突变情况是多种多样的。肿瘤类型也存在异质性，在亚组水平上报道了不同的作用。研究结果 02 总的来说，SMARCA4/BRG1功能及其调控的遗传途径对脑癌的潜在分子机制至关重要。BRG1在ATRT和WNT以及3mb组中发挥肿瘤抑制作用，功能缺失突变驱动肿瘤的发生和发展。相比之下，在SHH-MB和GBM中观察到BRG1活性促进癌症表型。SMARCA4突变在很大程度上取决于肿瘤和突变类型，具有不同的影响。ATPase结构域的杂合错义SMARCA4突变在WNT和3mb组中最常见，而在SHH和4mb组中很少发生突变。同样位于atp酶结构域的无义SMARCA4纯合突变在保留SMARCB1表达的ATRT肿瘤中最常被观察到。BRG1过表达在GBM中很常见，然而SMARCA4突变很少见，因此表达的改变很可能是通过其他可能是表观遗传的机制引起的。由于BRG1在脑癌中的异质性作用，很可能必须开发针对肿瘤类型子集中的特定突变的治疗方法。这将需要进一步了解brg1调控的肿瘤发展和进展的途径。合成致死率和小分子抑制剂的开发等策略显示出令人鼓舞的迹象，表明BRG1可以通过治疗干预成功靶向，CRISPR/Cas9基因编辑正在成为一种新策略;所有这些都有可能作为辅助治疗来改善目前脑癌的标准治疗方法。众所周知，染色质重塑是癌症基因表达程序的主要调节因子，因此，BRG1参与脑癌的知识和开发的靶向策略可能广泛适用于BRG1在肿瘤发生中具有明确作用的各种其他癌症类型，如肺癌、卵巢癌和前列腺癌。参考资料：https://www-nature-com.libproxy1.nus.edu.sg/articles/s41388-023-02773-9识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。