Assessing the role of understudied proteins as putative therapeutic targets for adenoid cystic carcinoma

About This Grant

Adenoid cystic carcinoma (ACC) of salivary glands is a rare, slow growing malignancy. Due to its insidious infiltrative growth pattern, ACC is often advanced by the time of clinical recognition, making it a difficult disease to treat. Current therapeutic options for primary localized ACC are restricted to surgery followed by radiotherapy with or without chemotherapy, as no systemic agent has been found to be effective in improving long-term disease control. Unfortunately, standard curative management has modest activity as most patients recur, largely due to ACC’s high tendency for perineural invasion and/or distant metastasis. Given its rarity, mechanisms that govern ACC pathogenesis remain poorly understood. Studies investigating new targeted therapies for ACC are hindered by the paucity of ACC specimens and preclinical cellular models. As a result, no FDA approved targeted treatments are currently available, and over 60% of the patients succumbing to the disease within 10 years of diagnosis. Development of the safe and effective targeted therapies is imperative for improving health outcomes and survival of patients with ACC. This proposal is specially designed in response to this notice of funding opportunity (NOFO) focusing on elucidating the role of understudied proteins in rare diseases. By coupling a large list of understudied proteins open for study under this NOFO with unique transcriptomic dataset of primary ACCs (a rare disease) and PandaOmics (a novel AI-driven therapeutic target discovery engine), we have selected HECTD2 and JMJD1C proteins as top-ranked putative therapeutic targets for ACC. While tangential previous findings pose HECTD2 and JMJD1C as potential drivers of certain types of cancer, their role in ACC tumorigenesis remains unknown, and thorough investigation is needed. In this project we will use a panel of authenticated and well characterized ACC cell lines and organoids, coupled with innovative proteomic approaches and comprehensive bioinformatics analysis of human specimens to address 3 objectives: (i) assess whether HECTD2 or JMJD1C deletion would induce anti-tumor activity in cellular models of ACC; (ii) map HECTD2 and JMJD1C protein interactome landscape; (iii) to define key HECTD2 or JMJD1C dependent signaling pathways that drive ACC tumorigenesis. These objectives are commensurate with the short-term nature of these research (one year), and specifically tailored to generate data critical for considering these proteins as potential candidates for therapeutic compound development against ACC. Given the devastating nature of ACC and dearth of effective treatment approaches, discovery of the previously unknown target candidates followed by the validation of their potential therapeutic activity in preclinical models (already available in our group) may ultimately translate to clinical trial settings and subsequently improve patients’ outcomes. As such, this pilot project is both innovative and clinically important.