Abstract 3166: Evaluation of genetic modulation of ACVR1 (aka ALK2) kinase gene as a clinical biomarker of the ACVR1 inhibitor TP-0184 (2019)

Abstract The receptor kinase ALK2, the product of the ACVR1 gene, is a member of the bone morphogenic protein (BMP) receptor family and a type I receptor of the greater TGFβ family. Germline mutations in ACVR1, and specifically the R206H manifestation, are a driving factor in the development of fibrodysplasia ossificans progressiva (FOP). Additionally, the childhood brain tumor, diffuse intrinsic pontine glioma (DIPG), is also associated with mutations in the ACVR1 gene including R206H, but accounts for approximately only 25% of DIPG. In adult cancers, mutations in the ACVR1 gene are observed, yet their role is less established. TP-0184 is a small molecule inhibitor of ACVR1 which inhibits the kinase activity of wild-type and mutant forms of ALK2. We examined the genetic make-up of ACVR1 mutations across large data sets to evaluate which mutations may portend benefit with TP-0184 treatment. Using publicly available sequence databases (e.g. cBioPortal, Cosmic, TCGA) we searched for ACVR1 mutations in tissues of cancer patients. Results were compared to the known mutations of ACVR1 in the literature associated with various cancers or demonstrate gain-of-function activity. Multiple mutations were found within ACVR1. The FOP community has done extensive work to identify and understand mutations that can drive aberrant activation of ACVR1. These mutations include L196P, R206H, Q207E, R258S, G328E/R, and G356D to name a few. ACVR1 mutations identified in adult cancers include many of these FOP mutations, but also demonstrate more diversity in their ACVR1 mutational profile with fewer “hotspots” and many mutations of unknown significance. For example, 8.49% (45/530) of endometrial cancer patients in the TCGA database have ACVR1 mutations, yet these are represented by 52 different mutations. The most common ACVR1 mutation in endometrial cancer is the bona fide R206H mutation, but it only makes up 0.9% of the 8.49% of ACVR1 mutations in endometrial cancer. If all ACVR1 mutations of known significance are considered, 2.45% of endometrial cancers have validated gain-of-function mutations in ACVR1. The remaining ACVR1 mutations in endometrial cancer are of unknown significance. Similar results were observed in other types of cancer such as melanoma, prostate and breast cancer and in other publicly available databases. The results from surveying these rare mutations in multiple cancer types will be presented. Since the BMP and TGFβ pathways are frequently dysregulated in cancers, the importance of any mutation that regulates ACVR1 activity in cancer may be an important regulator of tumorigenesis and a target of ACVR1 inhibitors. A Phase I trial with TP-0184 is in progress and will assess the correlation of ACVR1 mutations and compound clinical activity (Clinical trial information: NCT03429218). Further studies are in progress to assess the consequences and causal impact of ACVR1 mutations in cancer. Citation Format: Mark L. Wade, C Lars Mouritsen, Yuta Matsumura, Breeann V. Bryan, David J. Bearss, Steven L. Warner. Evaluation of genetic modulation of ACVR1 (aka ALK2) kinase gene as a clinical biomarker of the ACVR1 inhibitor TP-0184 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3166.