Optimizing Treatment for NF1-Deficient Metastatic ER+ Breast Cancers
Abstract
Despite great progress in treating estrogen receptor positive (ER+) breast cancer with standard endocrine therapy, in 2020 there are over 130,000 American living with ER+ metastasis, and 30,000 of them are expected to die annually. A key factor driving mortality is treatment resistance. Our parent DOD award aims to address therapeutic resistance by focusing on a gene called NF1 (neurofibromatosis type 1) because our clinical data demonstrated that when ER+ tumors have NF1 loss of function mutations, they exhibit resistance to tamoxifen and aromatase inhibition. Loss of one copy of the NF1 gene in all tissues from birth causes the common congenital condition neurofibromatosis type 1. Neurofibromatosis patients have higher incidence of many forms of malignancy including breast cancer, and NF1 is mutated in many cancers. Targeted therapy can revolutionize how cancer is treated because medication is tailored to a molecularly defined subset of patients sharing a common mechanism of tumor progression. Thus, for the targeted therapy to work, one must know what molecular activity drives progression of the tumor. NF1 is well-known to put a brake on a potent cancer driver called Ras — inactivated NF1 allows Ras to remain stuck in the “on” position, activating a number of downstream growth and survival signaling pathways. However, when we examined the mutation pattern in NF1 in our initial clinical studies, no mutations selectively inactivating the Ras regulatory region were found. Instead, the NF1 mutations that correlated with poor outcome created an NF1 null-like state, missing not only the Ras repression region but also other previously unknown functional regions that could be critical for aggressive tumor behavior. We subsequently made the entirely novel finding that NF1 not only represses Ras but, through an independent mechanism, also restrains the ability of ER to turn on the genes that drive breast cancer. Therefore, when NF1 is lost, cell growth and survival are greatly increased from the combined actions of derepressed Ras and ER, which may explain why NF1 loss is so lethal. To effectively treat NF1-deficient ER+ breast cancer, we determined that a combination of FDA-approved drugs inhibiting ER (fulvestrant) and the Ras pathway (binimetinib) must be used together, which results in full tumor regression in a patient-derived mouse model with this profile. As envisioned in the original DOD proposal, repurposing of an FDA-approved drug (binimetinib is used to treat melanoma) accelerates the development of a clinical protocol. We will soon launch a phase 2 randomized clinical trial approved by NCI’s ComboMATCH program. We will recruit metastatic ER+ NF1-deficient patients to be treated with fulvestrant + binimetinib combination in the experimental arm. The key objective of this Expansion Award is to support the execution of the trial to address the Overarching Challenge: “Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival.” To make the diagnosis of NF1-deficient ER+ breast cancer, we currently rely on tumor DNA sequencing to identify NF1 null-like mutations. Since we predict these will cause loss of the entire NF1 protein, simple immunohistochemistry for the NF1 protein (like the assay used for ER) should be an easier approach; however, poor antibody performance has hindered the development of a clinical assay. In Aim 1 we will address this problem by developing a mass spectrometry-based technology, which can directly detect NF1 with great sensitivity. Upon examination of our data from another trial (ATAC) with over 800 patients, we also discovered a new class of recurrent NF1 missense mutations associated with poor outcome after treatment with tamoxifen or anastrozole. Our current sequencing-based diagnosis, however, does not target missense mutations. To better inform of patient selection strategy and interpretation of treatment results, in Aim 2 we will
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110634
Entities
People
- Matthew J Ellis
Organizations
- Baylor College of Medicine
- United States Army