Discovering new cancer drugs
The overarching mission of the Cancer Molecular Therapeutics Program is to facilitate the discovery and development of new cancer therapeutic agents based on novel insights into cancer biology.
The program focuses on the early stages of the drug discovery process, from target validation through “proof-of concept” studies, which aims to demonstrate that a newly discovered drug candidate can successfully alter the course of cancer disease progression. This program brings together the complementary strengths and resources of its members and provides expertise in assay development, high throughput screening, downstream medicinal chemistry and pharmacology through its partnership with the Prebys Center.
By enabling cross-programmatic early translational efforts, we can leverage novel findings to identify and validate new targets for cancer, develop small molecule compounds to modulate identified targets, and test potential drug candidates in vitro and in state-of-the-art animal models of cancer.
– Michael Jackson, Ph.D., Program Director
A one-two punch to knockdown AML
Adams’ lab is developing novel combination therapies for Acute Myeloid Leukemia (AML). AML is a typically-lethal molecularly heterogeneous disease, with few broad-spectrum therapeutic targets. Unusually, most AML retain a normal TP53 gene, encoding the cell death protein p53, albeit in an inactive form. Drugs which activate this p53 and another class of drug called BET inhibitors both show encouraging pre-clinical activity, but limited clinical activity as single agents. Adams’ lab discovered enhanced toxicity of combined p53 activators and BET inhibitors towards AML in a culture dish and in mouse models. These results indicate that the combination of p53 activators and BET inhibitors is a novel candidate combination therapy justified for testing in human AML.
Resistant breast cancer - Blazing a new trail in options for early detection and treatment
Haricharan’s lab is developing novel approaches to overcome therapy resistance in breast cancer. Resistance to endocrine treatment occurs in ~30% of ER+ breast cancer patients resulting in ~40,000 deaths/year in the USA. Preclinical studies strongly implicate activation of a pro-growth protein, HER2 in endocrine treatment resistance. However, clinical trials of HER2 inhibitors in ER+/HER2- patients have disappointed, likely because we do not know which patients will respond to this combination. Haricharan’s lab discovered that loss of the most fundamental DNA damage repair pathway activates HER2 after endocrine treatment in ER+/HER2- breast cancer cells. Consequently, inhibiting HER2 in breast tumors that have defects in this DNA repair pathway restores sensitivity to endocrine treatment. Both diagnostic assays to test for defects in this DNA repair pathway and HER2 inhibitors are FDA-approved in cancer patients and can be easily used in the breast cancer context. Efforts are underway to initiate a clinical trial to translate these findings to the clinic.
Exposing epigenetic vulnerabilities to enhance immunotherapy response
Bradley is collaborating with Spruck (Tumor Initiation and Maintenance Program) to harness epigenetic dysregulation for immune therapy. Repetitive elements (REs), which include ancient retroviruses and retrotransposons embedded in our genomes, compose ∼50% of human DNA and are normally transcriptionally silenced, although the mechanism had remained elusive. Spruck’s lab identified FBXO44 as an essential repressor of REs in cancer cells. FBXO44 bound H3K9me3-modified nucleosomes at the replication fork and recruited an enzymatic complex that included H3K9me3 methyltransferase SUV39H1 to transcriptionally silence REs post-DNA replication. FBXO44/SUV39H1 inhibition reactivated REs, leading to DNA replication stress and stimulation of antiviral pathways and interferon (IFN) signaling in cancer cells to promote decreased tumorigenicity, increased immunogenicity, and enhanced immunotherapy response. Together, Bradley and Spruck showed that FBXO44 expression inversely correlated with replication stress, antiviral pathways, IFN signaling, and cytotoxic T cell infiltration in human cancers, while a FBXO44-immune gene signature predicted a favorable immunotherapy response in cancer patients. FBXO44/SUV39H1 were dispensable in normal cells indicating a therapeutic window for cancer treatment. Collectively, FBXO44/SUV39H1 are crucial repressors of RE transcription and their inhibition has antitumor potential as a stand-alone therapy or enhancer of immunotherapy.
FBXO44 promotes DNA replication-coupled repetitive element silencing in cancer cells.
Shen JZ, Qiu Z, Wu Q, Finlay D, Garcia G, Sun D, Rantala J, Barshop W, Hope JL, Gimple RC, Sangfelt O, Bradley LM, Wohlschlegel J, Rich JN, Spruck C
Cell 2021 Jan 21 ;184(2):352-369.e23
Tumor-penetrating therapy for β5 integrin-rich pancreas cancer.
Hurtado de Mendoza T, Mose ES, Botta GP, Braun GB, Kotamraju VR, French RP, Suzuki K, Miyamura N, Teesalu T, Ruoslahti E, Lowy AM, Sugahara KN
Nat Commun 2021 Mar 9 ;12(1):1541
BRD4-mediated repression of p53 is a target for combination therapy in AML.
Latif AL, Newcombe A, Li S, Gilroy K, Robertson NA, Lei X, Stewart HJS, Cole J, Terradas MT, Rishi L, McGarry L, McKeeve C, Reid C, Clark W, Campos J, Kirschner K, Davis A, Lopez J, Sakamaki JI, Morton JP, Ryan KM, Tait SWG, Abraham SA, Holyoake T, Higgins B, Huang X, Blyth K, Copland M, Chevassut TJT, Keeshan K, Adams PD
Nat Commun 2021 Jan 11 ;12(1):241
PSGL-1 attenuates early TCR signaling to suppress CD8(+) T cell progenitor differentiation and elicit terminal CD8(+) T cell exhaustion.
Hope JL, Otero DC, Bae EA, Stairiker CJ, Palete AB, Faso HA, Lin M, Henriquez ML, Roy S, Seo H, Lei X, Wang ES, Chow S, Tinoco R, Daniels GA, Yip K, Campos AR, Yin J, Adams PD, Rao A, Bradley LM
Cell Rep 2023 Apr 26 ;42(5):112436
Targeting epigenetic regulation for cancer therapy using small molecule inhibitors.
Kumar A, Emdad L, Fisher PB, Das SK
Adv Cancer Res 2023 ;158:73-161
Targeting the Dark Lipid Kinase PIP4K2C with a Potent and Selective Binder and Degrader.
Teng M, Jiang J, Wang ES, Geng Q, Toenjes ST, Donovan KA, Mageed N, Yue H, Nowak RP, Wang J, Manz TD, Fischer ES, Cantley LC, Gray NS
Angew Chem Int Ed Engl 2023 Apr 24 ;62(18):e202302364
Research Silos in Cancer Disparities: Obstacles to Improving Clinical Outcomes for Underserved Patient Populations.
Richardson A, Darst B, Wojcik G, Wagle N, Haricharan S
Clin Cancer Res 2023 Apr 3 ;29(7):1194-1199
Development of potent and selective degraders of PI5P4Kγ.
Ji W, Wang ES, Manz TD, Jiang J, Donovan KA, Abulaiti X, Fischer ES, Cantley LC, Zhang T, Gray NS
Eur J Med Chem 2023 Feb 5 ;247:115027
Characterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma.
Kameda-Smith MM, Zhu H, Luo EC, Suk Y, Xella A, Yee B, Chokshi C, Xing S, Tan F, Fox RG, Adile AA, Bakhshinyan D, Brown K, Gwynne WD, Subapanditha M, Miletic P, Picard D, Burns I, Moffat J, Paruch K, Fleming A, Hope K, Provias JP, Remke M, Lu Y, Reya T, Venugopal C, Reimand J, Wechsler-Reya RJ, Yeo GW, Singh SK
Nat Commun 2022 Dec 6 ;13(1):7506