PROJECT SUMMARY
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 we have identified first in class small
molecule inhibitors of hnRNP A18, a regulator of protein translation in cancer cells. hnRNP A18 targets
transcripts that are involved in cancer progression, metastasis, angiogenesis, anti-apoptosis and tumor
immune checkpoint. Our working hypothesis is that small molecule inhibitors of hnRNP A18 will inhibit the
translation of specific RNA transcripts devoted to conferring growth advantages and immune protection to
cancer cells. To verify this hypothesis three complementary specific Aims have been designed: Aim 1:
Design, synthesize and improve small molecule inhibitors of hnRNP A18. Aim 2: Prioritize compounds through
in vitro methods including RNA binding, cell reporter assay, proliferation and toxicity. Aim 3: Determine in vivo
anti-tumor and ADMET properties of lead compounds, employing, xenograft, syngeneic and Patients Derived
(PDX) tumors models. A multidisciplinary team of experts composed of medicinal chemists, structural
biologist, theoretical chemists, cancer biologist, immunologist and an oncologist has been assembled to
develop and optimize this new class of anticancer agents with the ultimate goal of bringing them into the clinic.