Characterization and Targeting NOTCH Activated Adenoid Cystic Carcinoma (ACC)
Abstract
Adenoid Cystic Carcinoma (ACC) is the second most common malignant salivary gland tumor. It has no known risk factors and it affects young patients (median 50 years old). In spite of aggressive local treatment with surgery and radiation, 40%-50% of patients will recur and eventually die as a consequence of disease. Currently there are no Food and Drug Administration (FDA)-approved targeted-therapy, immunotherapy, or “standard of care” chemotherapy to treat patients with metastatic disease. ACC therefore represent a major clinical unmet need. Based on the clinical observation of a subgroup of ACC patients (~20%) with very aggressive disease, we studied the DNA-fingerprint of a large number of ACC patients and discovered that a gene called NOTCH1 is frequently active in the most aggressive ACC. Notch1-active ACC has a propensity to metastasize to liver and bone, and is associated with shorter survival as compared to those patients with disease without Notch1 activation. Luckily, there are drugs that inhibit Notch1 and our findings led to the first clinical study investigating a potent Notch inhibitor (AL101) in metastatic ACC patients whose tumors carry NOTCH activating mutations. Interim results of this study showed AL101 benefited a subset of patients, with 22% experiencing significant tumor shrinkage and 39% having disease stability. Notably, a significant proportion of patients had mixed responses, with some sites of tumor improving and other areas worsening. The significant tumor heterogeneity observed in the Notch1-ACC patients and the limited activity with Notch inhibitor as single agent suggests that combination therapies (i.e., combine AL101 with other drugs) are needed to kill diverse tumor cells and overcome AL101 drug resistance. In order to understand more about the biology of ACC and develop rational therapeutic drugs combinations, we conducted a comprehensive molecular analysis of a large ACC cohort and identified multiple proteins that are expressed at high levels exclusively in the Notch1-ACC subgroup, providing unique therapeutic opportunities. Importantly, there is a growing body of evidence showing that the immune cells within and surrounding tumors, also called the tumor immune microenvironment, and their interactions with the tumor cells impact diverse aspects of tumor biology and therapy response. Therefore, development of co-targeting approaches for the aggressive Notch1-ACC subset should consider the co-alteration status of other tumors proteins and its surrounding immune cells, which have not yet been characterized. Our project aims to (1) assess the Notch1-ACC immune microenviroment and explore how it may affect patient’s outcomes, (2) determine the molecular changes in the ACC tumor and its immune microenvironment induced by a Notch inhibitor (AL101) and assess the safety and activity of a short-course of AL101 (6-8 weeks) given to patients with Notch1-ACC prior to standard of care surgery in a clinical trial, and (3) develop more effective therapy for ACC patients with Notch1 activation guided by our discoveries from Aims 1 and 2 by testing AL101 combined with other drugs in pre-clinical models derived from patients in the clinical trial (cancer organoids and mouse models implanted with patient’s tumors). The novelty of our proposal includes the first “window of opportunity” trial in ACC that takes advantage of the tumor obtained during pre-planned surgery to assess the effect of a drug (AL101) in the tumor and its immune microenvironment and compare with the pre-treatment tumor specimen obtained by a biopsy. We will also pioneer the use of ACC patient-derived organoids and humanized mice using clinical trial patients’ samples to test combinatorial therapy. We expect the most promising combination identified in the humanized mouse studies will be tested in a clinical study for Notch1-active ACC. As physicians and scientists who care for ACC patients and study this orphan disease,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110409
Entities
People
- Renata Ferrarotto
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army