Targeting Basal-Like Prostate Cancer with Cadherin 3 Antibody-Drug Conjugate as Single Agent and in Combination with Immunotherapy
Abstract
Rationale, Objective and Aims: Recent studies show that prostate cancer can be classified as luminal-like and basal-like subtypes based on the overall expression pattern of the genes. Among the prostate cancer patients, basal-like subtype accounts for 30 to 40% of Caucasian men, but over 60% of African American men. Androgen receptor expression is much lower in basal-like than luminal-like subtype, which may explain why basal-like prostate cancer exhibits poor postoperative response to androgen-deprivation therapy. However, how do you target basal-like prostate cancer, a disease inherently less sensitive to the mainstay of prostate cancer therapy? This represents a critical yet unmet clinical need because basal-like gene expression is shown to be associated with metastatic castration-resistant prostate cancer (CRPC), the most lethal form of prostate cancer. Recently, we found that a protein called CDH3 was dramatically upregulated in a specific transgenic mouse model of prostate cancer. This model activates the Wnt signal pathway that is known to promote the basal-like property of the cells. We also found strong cell surface expression of CDH3 in a variety of other human prostate cancer models, all of which are negative for androgen receptor. Therefore, CDH3 emerges as a potential marker of basal-like androgen-receptor-low prostate cancer. Antibody-drug conjugate (ADC) is an innovative class of biopharmaceutical drugs to kill cancer cells expressing specific tumor-associated cell surface markers. CDH3 is a promising target for ADC development. Even though there are five Food and Drug Administration-approved ADCs for cancer treatment, no ADCs are approved for treating PCa yet. Some ADCs were shown to sensitize tumors to immunotherapy, a strategy potentially exploitable to overcome the strong resistance of metastatic CRPC to immunotherapy. The objective of our project is to develop a novel, effective, safe, and personalized therapeutic strategy for treating basal-like lethal CRPC. We have preliminary data to show that a newly developed CDH3-targeted ADC killed CDH3high, but not CDH3low, prostate cancer cells. To investigate the translational potential of this new CDH3-ADC, we propose to accomplish three Specific Aims: (1) Identify the role of Wnt signaling in CDH3 upregulation and basal-like phenotype using mouse and human prostate cancer models as well as clinical samples. Both genetic modifications in experimental systems and clinical association studies will be conducted to define the mechanism of CDH3 overexpression and basal-like phenotype. (2) Determine the effect of CDH3-ADC in comparison with docetaxel on primary and metastatic CRPC. Docetaxel chemotherapy is the standard of care for patients with CRPC, but it only extends survival by 2-3 months. We will use a variety of human prostate cancer models (both in cell culture and in mice) to determine whether CDH3-ADC outperforms docetaxel in treating primary and bone metastatic CRPC that is positive for CDH3 expression. (3) Improve the response of CDH3 positive prostate cancer to immunotherapy by combining immunotherapy and CDH3-ADC. We will first identify the potential of CDH3-ADC to enhance immunotherapy by examining if CDH3-ADC triggers immunogenic cell death to activate immune cells. Next, we will use three independent immune-competent mouse models of lethal CRPC to determine whether CDH3-ADC promotes the efficacy of anti-PD1 antibody, which is a highly successful immunotherapy for treating over 10 other types of cancer (prostate cancer is not included due to resistance). Applicability of the Research: Our research addresses three of the Fiscal Year 2019 Prostate Cancer Research Program Overarching Challenges. First, by unraveling the mechanism on how CDH3 is upregulated at the molecular level in basal-like prostate cancer, we will help define the biology of lethal prostate cancer to reduce mortality. Second, by elucidating the a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010312
Entities
People
- Xin Lu
Organizations
- United States Army
- University of Notre Dame