Neuroendocrine neoplasm of lung

Medical researchers found a way to grow samples of different types of neuroendocrine tumors (NETs) in the lab. While generating their new model, the researchers discovered that some pulmonary NETs need the protein EGF to be able to grow. These types of tumors may therefore be treatable using inhibitors of the EGF receptor. The Organoid Group (Hubrecht Institute) and the Rare Cancers Genomics Team (IARC/WHO) found a way to grow samples of different types of neuroendocrine tumors (NETs) in the lab. While generating their new model, the researchers discovered that some pulmonary NETs need the protein EGF to be able to grow. These types of tumors may therefore be treatable using inhibitors of the EGF receptor. The results were published in Cancer Cell on 11 December 2023. Neuroendocrine tumors Neuroendocrine tumors (NETs) are relatively rare tumors that can be slow-growing. However, some NETs can be aggressive and hard to treat. It is not yet possible to predict which tumors will become aggressive. There are very few models to study NETs in the lab, which limits research into this type of tumor. New disease model Researchers from the Organoid Group (Hubrecht Institute) and the Rare Cancers Genomics Team (IARC/WHO) therefore set out to develop new models to study NETs. They derived cells from patients with NETs and were able to culture them into 3D structures called organoids. These organoids mimic the behavior of actual NETs and can therefore be used to study this type of tumor in the lab. The new model is the first organoid model of the disease. Growth factor While generating the organoids, the researchers found that some pulmonary NETs need a protein called the Epidermal Growth Factor (EGF) to grow. "If we inhibit the receptor for EGF, some organoids die. Apparently, these organoids are dependent on EGF for their survival," says Talya Dayton, co-first author on the paper published in Cancer Cell. "We need further research to confirm our findings, but this may indicate that patients with EGF-dependent NETs could be treated with inhibitors of the EGF receptor." Inhibitors of the EGF receptor are already a course of treatment for other types of tumors. Aggressive tumors Tumors are usually thought to be independent of growth factors. That some NETs turn out to be dependent on the growth factor EGF is therefore surprising. "We think that their EGF-dependence might explain, in part, why some of these tumors grow slowly. We also think this might mean that one of the ways in which NETs can become aggressive is by becoming growth-factor independent. If they no longer need the growth factor, their growth may accelerate" Dayton explains. Potential new therapy The newly developed model for NETs provides a new way to study the disease in the lab. Dayton: "This allows us and other scientists to understand the biology of these tumors so we can hopefully find effective therapies." Although further research is needed, the model already points to a new route of treatment for patients with pulmonary NETs.

BI 764532 is an investigational T-cell engager that redirects T cells towards cancer cells expressing the DLL3 protein DLL3 antigen was discovered using OBT’s proprietary OGAP® drug discovery platform This is the third Fast Track designation for BI 764532 Oxford, UK, San Jose, Calif., 29 November 2023 – Oxford BioTherapeutics (OBT), a clinical stage oncology company with a pipeline of immuno-oncology and Antibody Drug Conjugate (ADC)-based therapies, today announces that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to BI 764532 for the potential treatment of advanced or metastatic large-cell neuroendocrine carcinoma of the lung (LCNEC-Lung) expressing DLL3 whose disease has progressed following at least one prior line of treatment including platinum-based chemotherapy. BI 764532 is an investigational DLL3/CD3 IgG-like T-cell engager for potential treatment of patients with LCNEC-Lung that is being developed by Boehringer Ingelheim. The discovery of BI 764532 (OBT620) was enabled through a successful partnership initiated in 2013, leveraging OBT’s proprietary OGAP® drug discovery platform for identification of the DLL3 antigen and Boehringer Ingelheim’s longstanding expertise in oncology and development of biotherapeutics. As of November 2023, the FDA granted Fast Track designation to BI 764532 for the potential treatment of extensive-stage small cell lung cancer (SCLC) whose disease has progressed following at least two prior lines of treatment including platinum-based chemotherapy, and of advanced or metastatic extrapulmonary neuroendocrine carcinomas (epNEC) whose disease has progressed following at least one prior line of treatment including platinum-based chemotherapy. BI 764532 was also granted Orphan Drug designation by the FDA for the treatment of SCLC, and is currently being investigated in a Phase 2 study, ‘DAREON™-5’ (NCT05882058), in patients with relapsed/refractory extensive-stage SCLC and other relapsed/refractory NEC. Christian Rohlff, Chief Executive Officer of OBT, commented: “We are delighted about the clinical development to help address unmet needs for people living with small cell lung cancer and other neuroendocrine carcinomas. This is an important milestone for our teams and exciting news for the community” FDA’s Fast Track designation is designed to facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening diseases and that demonstrate the potential to address unmet medical needs. *** About Oxford BioTherapeutics Oxford BioTherapeutics (OBT) is a clinical stage oncology company with a pipeline of first-in-class immuno-oncology (IO) and antibody-drug conjugate (ADC) based therapies designed to fulfil major unmet patient needs in cancer therapeutics. These include bispecific, Chimeric Antigen Receptor T Cell (CAR-T), Antibody Drug Conjugate (ADC) and Antibody Dependent Cell-mediated Cytotoxicity (ADCC) therapeutics. OBT's first clinical program, OBT076, initiated expansion in a US Clinical Trial in 2021 in patients with advanced or refractory solid tumors, including gastric, bladder, ovarian and lung cancer, where CD205 is overexpressed. Infiltration of tumors by immunosuppressive cells correlates with adverse outcomes (lower progression free and overall survival), suggesting that this process contributes to the progression of several cancers. OBT’s proprietary OGAP® target discovery platform is based on one of the world’s largest proprietary cancer membrane proteomic databases, with data on over 5,000 cancer cell proteins providing unique, highly qualified oncology targets, of which three programs are in clinical development in the US and Europe. OBT's IO discovery process provides unique insights into the cancer-immune cell synapse and has identified several novel IO monoclonal and bispecific antibody candidates for cancer therapies. OBT’s pipeline and development capabilities have been validated through multiple strategic partnerships including with Boehringer Ingelheim, ImmunoGen and our cell therapy research collaboration with Kite Pharma as well as other world leaders in antibody development (such as Amgen, WuXi, Medarex (BMS), Alere (Abbott) and BioWa). OBT has a strong oncology focused management team and board with significant experience in developing IO and antibody-based therapies. For more information on Oxford BioTherapeutics, please visit www.oxfordbiotherapeutics.com/ and follow us on LinkedIn. ContactsInvestors:Dr Christian Rohlff, CEOchristian.r@oxfordbiotherapeutics.com Media:MEDiSTRAVA ConsultingSylvie Berrebi, Sandi Greenwood, Erica HollingsworthE : OBT@medistrava.comT : +44 (0) 203 928 6900

Preclinical data demonstrate preferential activity of MRT-2359, an orally bioavailable GSPT1-directed molecular glue degrader, in MYC-driven tumor cells Phase 1/2 clinical trial of MRT-2359 ongoing in MYC-driven solid tumors, including lung cancer; disclosure of initial data from Phase 1 arm of study expected in second half of 2023 BOSTON, April 17, 2023 (GLOBE NEWSWIRE) -- Monte Rosa Therapeutics, Inc. (NASDAQ: GLUE), a clinical stage biotechnology company developing novel molecular glue degrader (MGD)-based medicines, today presented preclinical data characterizing MRT-2359, an orally bioavailable GSPT1-directed molecular glue degrader designed for the treatment of MYC-driven solid tumors, including lung cancer. The data were presented at the American Association for Cancer Research (AACR) Annual Meeting in Orlando, FL. “Our extensive preclinical work on MRT-2359 forms a strong basis for our ongoing clinical trial by providing insight into the effects of GSPT1 degradation on the MYC pathway in cancer. By optimizing selectivity and fine-tuning the degradation rate of the translation termination factor GSPT1, using AI tools built into our QuEEN™ platform, we generated a GSPT1 degrader with preferential effect on MYC-driven tumors, and showed this effect is unique compared to other modalities targeting the protein translation machinery. We look forward to reporting initial data from the Phase 1 arm of the trial later this year,” said Owen Wallace, Ph.D., Chief Scientific Officer of Monte Rosa. A summary of our data and findings includes: Anti-tumor activity of MRT-2359 was assessed in >80 lung patient-derived xenografts (PDXs) confirming the preferential anti-tumor activity in PDX models of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) where N- and/or L-MYC expression was high, as well as in PDX models of neuroendocrine (NE) lung cancer. Numerous instances of tumor regressions were observed in these models with MRT-2359 when dosed orally daily or intermittently A causal link was established in vitro between N- and L-MYC expression and sensitivity to MRT-2359; other agents targeting the protein translation machinery or MYC transcription (e.g., CDK9 inhibitor) failed to show differential activity Treatment with MRT-2359 in the N- or L-MYC high cell lines inhibited protein translation and caused a downmodulation of transcription of MYC target genes MRT-2359 had preferential activity over the growth and survival of MYC-driven tumor cells, compared with cell lines with low N- or L-MYC expression, in which little effect was observed following GSPT1 degradation Collectively, these data support the ongoing clinical evaluation of MRT-2359. Initiated in October 2022, the Phase 1/2 open-label, multicenter study (Identifier: NCT05546268) is primarily assessing the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and preliminary clinical activity of MRT-2359 in patients with previously treated selected solid tumors, including NSCLC, SCLC, high-grade neuroendocrine cancer of any primary site, diffuse large B-cell lymphoma (DLBCL) and solid tumors with L-MYC or N-MYC amplification. In the Phase 1 portion of the study, patients are receiving escalating doses of MRT-2359 to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Once the RP2D is determined, the anti-tumor activity of MRT-2359 will be assessed as part of the Phase 2 portion of the study, which includes molecular biomarkers for patient stratification and selection. The preclinical data were presented as follows: Oral Presentation Title: New Drugs on the Horizon - Discovery of MRT-2359, an orally bioavailable GSPT1 molecular glue degrader, for MYC-driven cancers Session: New Drugs on the Horizon: Part 3 Presenter: Owen Wallace, Ph.D., Chief Scientific Officer of Monte Rosa Date and Time: Monday, April 17; 10:40 a.m. ET Oral Presentation Title: Development of MRT-2359, an orally bioavailable GSPT1 molecular glue degrader, for the treatment of lung cancers with MYC-induced translational addiction Session: Mini Symposium Abstract: 3449 Presenter: Gerald Gavory, Ph.D., Senior Director of Drug Discovery and Translational Research at Monte Rosa Date and Time: Monday, April 17; 3:10 p.m. ET About MRT-2359 MRT-2359 is a potent, selective and orally bioavailable molecular glue degrader (MGD) that induces the interaction between the E3 ubiquitin ligase component cereblon and the translation termination factor GSPT1, leading to the targeted degradation of GSPT1 protein. The MYC transcription factors (c‑MYC, L-MYC and N-MYC) are well-established drivers of human cancers that maintain high levels of protein translation, which is critical for uncontrolled cell proliferation and tumor growth. Preclinical studies have shown that this addiction to MYC-induced protein translation creates a dependency on GSPT1. By inducing degradation of GSPT1, MRT-2359 exploits this vulnerability, disrupting the protein synthesis machinery and leading to anti-tumor activity in MYC-driven tumors. About Monte Rosa Monte Rosa Therapeutics is a biotechnology company developing novel molecular glue degrader (MGD) medicines for patients living with serious diseases such as oncology, autoimmune and inflammatory diseases. MGDs are small molecule protein degraders designed to employ the body’s natural mechanisms to selectively eliminate therapeutically relevant proteins. The Company’s QuEEN™ (Quantitative and Engineered Elimination of Neosubstrates) platform enables it to rapidly identify protein targets and design highly selective degraders by combining diverse libraries of proprietary MGDs with in-house proteomics, structural biology, AI/machine learning, and computational chemistry capabilities. For more information, visit Forward-Looking Statements This communication includes express and implied “forward-looking statements,” including forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward looking statements include all statements that are not historical facts, and in some cases, can be identified by terms such as “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “intend,” “plan,” “objective,” “anticipate,” “believe,” “estimate,” “predict,” “potential,” “continue,” “ongoing,” or the negative of these terms, or other comparable terminology intended to identify statements about the future. Forward-looking statements contained herein include, but are not limited to, statements about our ongoing pre-clinical and clinical development of our GSPT1 degrader referred to as MRT-2359, including our expectations regarding the potential relevance of certain pre-clinical observations for continued clinical development, and our expectations for the nature and timing of our clinical development of MRT-2359. By their nature, these statements are subject to numerous risks and uncertainties, including those risks and uncertainties set forth in our most recent Annual Report on Form 10-K for the year ended December 31, 2023, filed with the US Securities and Exchange Commission on March 16, 2023, and any subsequent filings, that could cause actual results, performance or achievement to differ materially and adversely from those anticipated or implied in the statements. You should not rely upon forward looking statements as predictions of future events. Although our management believes that the expectations reflected in our statements are reasonable, we cannot guarantee that the future results, performance or events and circumstances described in the forward-looking statements will be achieved or occur. Recipients are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date such statements are made and should not be construed as statements of fact. We undertake no obligation to publicly update any forward-looking statements, whether as a result of new information, any future presentations or otherwise, except as required by applicable law. Investors Shai Biran, Monte Rosa Therapeutics ir@monterosatx.com Media media@monterosatx.com