W. Nathaniel (Nate) Brennen, PhD

Primary Academic Title

Associate Professor of Oncology

Background

Additional Academic Titles

Associate Professor of Physiology, Pharmacology and Therapeutics, Associate Professor of Urology

Research Interests

FAP, carcinoma-associated fibroblasts (CAFs), Fibroblasts, MSCs, prodrugs, Epigenetics, LSD1, Prostate Cancer, Stroma, Therapy, Tumor Microenvironment (TME), patient-derived xenografts (PDXs), patient-derived models, advanced preclinical models, drug development

Lab Website

Brennen Lab

• As a pharmacologist, my long-term goal is to make a significant contribution to curing prostate cancer (PCa). To achieve this goal, my laboratory takes a rigorous, multi-disciplinary, modality-agnostic, collaborative team-based approach towards developing innovative therapeutic and prognostic strategies with an emphasis on exploiting vulnerabilities within the tumor microenvironment (TME). Towards this goal, we are strategically pursuing multiple parallel avenues for drug discovery and development, including stromal-targeted produgs, protoxins, and radiolabeled antibodies, in addition to cell-based therapy and systemic drug delivery platforms; all of which are designed to reduce toxicity to peripheral non-target tissues (i.e. side effects) while maximizing anti-tumor efficacy (i.e. therapeutic benefit).

  I have nearly 20 years of experience in the development of novel therapeutic strategies for mCRPC. One such strategy was recently awarded two U.S. patents, and I am listed as an inventor on several more that are currently being examined. This intellectual property is the basis for a 2020 startup company - Abida Bio, LLC - spun out of Hopkins Oncology and founded on the development of a new biopharmaceutical drug category - "osmotics". Additionally, I have expertise in the development and characterization of new preclinical animal models for assessing therapeutic efficacy and safety, including novel models of liver metastasis and patient-derived xenografts (PDXs) representing the full spectrum of lethal mCRPC observed clinically. I have an established track-record of productivity and history of effective collaboration with leaders not only at Johns Hopkins, but also at leading academic centers and biopharmaceutical companies nationally and worldwide to facilitate efficient translation of promising therapeutic strategies from the preclinical space to the bedside.

Research Summary

Our laboratory is based in the Cancer Invasion & Metastasis and Prostate Cancer programs of the Department of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins School of Medicine in Baltimore, MD.

We take a rigorous, multi-disciplinary, modality-agnostic, collaborative team science-based approach towards developing innovative therapeutic, prognostic, and predictive strategies for prostate cancer. Towards this goal, our team places an emphasis on exploiting vulnerabilities within the tumor microenvironment (TME), particularly focused on fibroblast activation protein (FAP), or inducing synthetic lethal pathways through epigenetic manipulation of essential regulatory programs. Though significant progress has been made in recent years, prostate cancer still kills ~35,000 U.S. men annually (1 in 44) with an additional 100,000 suffering from painful bone metastases once the disease progresses to the incurable metastatic castration-resistant state (i.e., mCRPC) based on 2024 ACS statistics. This is the most commonly diagnosed non-skin cancer in American men (impacting 1 in 8 during their lifetime with ~300,000 new diagnoses each year) and 2nd leading cause of cancer-related deaths in men behind lung cancer.

To accomplish these goals, we are strategically pursuing innovative therapeutic platforms, including stromal-targeted prodrugs, protoxins, small molecules, and antibodies, in addition to epigenetic modulators and novel drug delivery systems; all of which are designed to reduce toxicity to peripheral non-target tissue (i.e., side effects) while maximizing anti-tumor efficacy (i.e., therapeutic benefit).

I have more than 20 yrs of experience in the development of novel therapeutic strategies for mCRPC. In addition to drug development, I have expertise in the development and generation of advanced animal models, and alternative approaches for assessing therapeutic efficacy and safety, including novel models of liver metastasis and patient-derived xenografts (PDXs) and organoids (PDOs). Indeed, over the last decade we have developed and characterized >15 new PDXs derived from metastatic lesions in mCRPC patients. Many of these PDXs/PDOs/PDXOs represent emerging highly aggressive treatment-resistant phenotypes that are underrepresented in other prostate cancer PDX collections and thus, represent a valuable and unique resource that we share openly with other investigators.

My laboratory routinely performs biochemical assays related to target inhibition and enzyme kinetics, genetic manipulation for target validation, analysis of standard pharmacokinetic and pharmacodynamic (PK/PD) parameters to assess biodistribution, clearance, and target engagement, in addition to in vivo efficacy and toxicity using state-of-the-art and clinically-representative models such as those described above. I have an established track-record of productivity and history of collaboration with leaders not only at Johns Hopkins, but also leading academic centers and biopharmaceutical companies nationally and worldwide to facilitate efficient translation of promising therapeutic strategies from the preclinical space to the bedside. We maintain close relationships with our medical oncology colleagues to maximize translational potential and clinical relevance.

PubMed - Publications

http://www.ncbi.nlm.nih.gov/sites/myncbi/1VwW4hpl7Uck0/bibliography/45920774/public/?sort=date&direction=descending

Selected Publications

• WN Brennen, DM Rosen, H Wang, JT Isaacs, SR Denmeade, Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug. Journal of the National Cancer Institute 104 (17), 1320-1334

• WN Brennen, JT Isaacs, SR Denmeade, Rationale behind targeting fibroblast activation protein–expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy. Molecular cancer therapeutics 11 (2), 257-266

• WN Brennen, Y Zhu, IM Coleman, SL Dalrymple, L Antony, RA Patel, et al. Resistance to androgen receptor signaling inhibition does not necessitate development of neuroendocrine prostate cancer. JCI insight 6 (8)

• TEG Krueger, DLJ Thorek, SR Denmeade, JT Isaacs, WN Brennen. Concise review: mesenchymal stem cell-based drug delivery: the good, the bad, the ugly, and the promise. Stem cells translational medicine 7 (9), 651-663

• Y Zhu, SL Dalrymple, I Coleman, SL Zheng, J Xu, JE Hooper, et al. Role of androgen receptor splice variant-7 (AR-V7) in prostate cancer resistance to 2nd-generation androgen receptor signaling inhibitors. Oncogene 39 (45), 6935-6949