National Cancer Institute 3R01CA285468-03S1

First in Class Small molecules to simultaneously inhibit protein translation and an immune checkpoint in cancers

This NIH grant funds research to develop first-in-class small molecule inhibitors targeting hnRNP A18, a protein involved in cancer progression and immune checkpoint regulation, aiming to improve cancer therapy by reducing toxicity and resistance.

Description

Therapeutic approaches in cancer therapies have evolved from the use of highly toxic chemotherapy agents to precision medicine with well-defined targets and minimal toxicities. While precision medicine is highly desirable, its effectiveness depends on the presence of the activating agents and typically target a single pathway which is conducive to the development of drug resistance when alternative pathways and or feedback mechanisms are used. These limitations are best exemplified by anti-cancer therapies targeting the protein translation regulator mammalian Target Of Rapamycin (mTOR). Although these inhibitors show clear benefit in some cancers such as mantle cell lymphomas, Renal Cell Carcinoma and Tuberous Sclerosis Complex-related tumors they have limited efficacy as single agents in most other cancers due to compensatory feedback mechanisms. In addition, targeting components of the general protein translational machinery that are also essential for normal cell functions would likely contribute to normal tissue toxicity. Agents that could target simultaneously a number of limited key pathways essential for cancer cells progression and survival would thus be expected to decrease toxicity and resistance. To this aim, first-in-class small molecule inhibitors of hnRNP A18, a regulator of protein translation in cancer cells, have been identified. hnRNP A18 targets transcripts involved in cancer progression, metastasis, angiogenesis, anti-apoptosis, and tumor immune checkpoint. The working hypothesis is that small molecule inhibitors of hnRNP A18 will inhibit the translation of specific RNA transcripts that confer growth advantages and immune protection to cancer cells.

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