Abstract Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. The median overall survival (OS) of GBM patients is poor (1-2 years) with standard of care therapies, demonstrating the significant need for the development of novel therapeutics. TNG908 is a clinical stage MTA-cooperative PRMT5 inhibitor that is selectively active in MTAP-deleted cells by leveraging a synthetic lethal interaction. Approximately 40% of GBM tumors have MTAP loss due to a co-deletion event with the proximal tumor suppressor gene, CDKN2A. In preclinical in vitro studies, TNG908 was 15-fold more potent in MTAP-deleted cancer cell lines than in MTAP WT cells. TNG908 has high passive permeability and is neither a substrate for P-glycoprotein nor Breast Cancer Resistant Protein (BCRP) efflux transporters. Consistent with these favorable attributes, TNG908 demonstrated in vivo brain penetration in multiple preclinical models, including non-human primates and mice. TNG908 on-target pharmacodynamic activity was determined by dose-dependent decreases in SDMA-modified protein levels in a GBM subcutaneous xenograft model. TNG908 demonstrated dose-dependent antitumor activity in multiple hyper- and hypomethylated GBM subcutaneous models, including cell lines and patient-derived xenograft models. Despite 6-fold reduced Kpuu in rodents (Kpuu ~0.15) relative to non-human primates (Kpuu 0.9), oral administration of TNG908 drove near tumor stasis and increased median survival by 3-fold in a highly aggressive murine GBM orthotopic model. In summary, TNG908 is a potent, brain-penetrant, MTA-cooperative PRMT5 inhibitor that drives strong antitumor activity in preclinical models of MTAP-deleted GBM. TNG908 is currently enrolling patients with MTAP-deleted tumors including glioblastoma in a Phase I/II clinical trial (NCT05275478).
Medulloblastoma is an embryonal tumor thought to arise from the granule cell precursors (GCPs) of the cerebellum. PATCHED ( PTCH ), an inhibitor of Hedgehog signaling, is the best-characterized tumor suppressor in medulloblastoma. However, <20% of medulloblastomas have mutations in PTCH . In the search for other tumor suppressors, interest has focused on the deletion events at the 17p13.3 locus, the most common genetic defect in medulloblastoma. This chromosomal region contains HYPERMETHYLATED IN CANCER 1 ( HIC1 ), a transcriptional repressor that is a frequent target of epigenetic gene silencing in medulloblastoma. Here we use a mouse model of Ptch1 heterozygosity to reveal a critical tumor suppressor function for Hic1 in medulloblastoma. When compared with Ptch1 heterozygous mutants, compound Ptch1/Hic1 heterozygotes display a fourfold increased incidence of medulloblastoma. We show that Hic1 is a direct transcriptional repressor of Atonal Homolog 1 ( Atoh1 ), a proneural transcription factor essential for cerebellar development, and show that ATOH1 expression is required for human medulloblastoma cell growth in vitro. Given that Atoh1 is also a putative target of Hh signaling, we conclude that the Hic1 and Ptch1 tumor suppressors cooperate to silence Atoh1 expression during a critical phase in GCP differentiation in which malignant transformation may lead to medulloblastoma.
Abstract The concept of synthetic lethality has long held promise for the next generation of genetically targeted cancer therapies to follow the success of PARP inhibitors in the treatment of BRCA-mutant cancers. The classical definition of synthetic lethality arose in Drosophila with the observation that loss of either of two genes independently had little effect on cell viability but loss of both led to cell death. This definition has now been expanded to capture pairs of genes in which genetic alteration of one gene and pharmacological inhibition of the other leads to death of cancer cells while sparing the normal cells which lack the genetic alteration, leading to a broad therapeutic index. Functional genomics screening (using unbiased RNAi or CRISPR-based technology) has enabled the systematic discovery of novel synthetic lethal targets for drug discovery. The selective dependence of MTAP-deleted cells on PRMT5 is one of the strongest genetic interactions observed in early RNAi screens. Approximately 10-15% of all human cancer is MTAP-deleted, providing a large and diverse patient population. MTA-cooperative PRMT5 inhibitors, which bind preferentially in the presence of MTA, have been developed by scientists at Tango Therapeutics and elsewhere to leverage the synthetic lethal relationship between PRMT5 and MTAP loss. MTA-cooperative PRMT5 inhibitors inhibit PRMT5 in MTAP-deleted cancer cells and spare MTAP-expressing normal cells leading to clinically well-tolerated and efficacious therapies. MTA-cooperative PRMT5 inhibitors have broad therapeutic potential both as single agent and in combination with other therapies. Citation Format: Kimberly Briggs.Leveraging synthetic lethality for the development of novel cancer therapies. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA002.
The ability to induce pluripotent stem cells from committed, somatic human cells provides tremendous potential for regenerative medicine. However, there is a defined neoplastic potential inherent to such reprogramming that must be understood and may provide a model for understanding key events in tumorigenesis. Using genome-wide assays, we identify cancer-related epigenetic abnormalities that arise early during reprogramming and persist in induced pluripotent stem cell (iPS) clones. These include hundreds of abnormal gene silencing events, patterns of aberrant responses to epigenetic-modifying drugs resembling those for cancer cells, and presence in iPS and partially reprogrammed cells of cancer-specific gene promoter DNA methylation alterations. Our findings suggest that by studying the process of induced reprogramming, we may gain significant insight into the origins of epigenetic gene silencing associated with human tumorigenesis, and add to means of assessing iPS for safety.
Abstract MTAP deletions occur in 10-15% of all human cancers, which provides one of the largest precision oncology patient populations. MTA-cooperative PRMT5 inhibitors leverage the well-characterized synthetic lethal relationship between PRMT5 inhibition and MTAP deletion. TNG908 is a clinical stage MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted solid tumors. TNG462 is an investigational stage MTA-cooperative PRMT5 inhibitor with significantly enhanced potency, selectivity, and extended target coverage designed to be a best-in-class treatment for patients with MTAP-deleted cancer. In vitro, TNG462 is 45X selective for MTAP-deleted cancer cell lines over isogenic MTAP WT cell lines and has marked selectivity for MTAP-deleted cancer cell lines independent of lineage in a large, diverse cell line panel. Oral administration of TNG462 drives dose-dependent antitumor activity including durable tumor regressions and complete responses in cell line- and patient-derived xenograft models representative of clinically relevant histologies. Preclinical data suggest a low risk for drug-drug interactions, supporting clinical combination strategies. With enhanced potency and selectivity for MTAP-deleted cancer cells and improved pharmacokinetic properties to extend target coverage, TNG462 has the potential for broader and deeper clinical activity in MTAP-deleted solid tumors than the MTA-cooperative PRMT5 currently being evaluated in clinical trials. Citation Format: Kimberly J. Briggs, Alice Tsai, Minjie Zhang, Matthew R. Tonini, Brian Haines, Alan Huang, Kevin M. Cottrell. TNG462 is a potential best-in-class MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4970.
