Molecule Targets Vulnerability in Triple-Negative Breast Cancer : Oncology Times

Journal Logo


Molecule Targets Vulnerability in Triple-Negative Breast Cancer

Kumar Das, Dibash PhD

Oncology Times 44(19):p 19, October 5, 2022. | DOI: 10.1097/01.COT.0000891824.29878.c9
  • Free

Triple-negative breast cancer (TNBC), negative for the expression of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2, account for approximately 15-20 percent of new breast cancer diagnoses. Women with TNBC have a higher propensity to have a more aggressive clinical course and a poor outcome due to a lack of actionable therapeutic targets. Thus, there is an urgent and unmet need for the development of novel therapeutic strategies.

In a study published in Nature Cancer, a scientific team has identified a new compound that kills a range of hard-to-treat cancer types, including TNBC, by exploiting specific vulnerabilities in cancer cells not previously targeted by other drugs (2022; Researchers included Jung-Mo Ahn, PhD, Associate Professor of Chemistry at The University of Texas at Dallas; Ganesh Raj, MD, PhD, The Dr. Paul Peters Chair in Urology in Memory of Rumsey and Louis Strickland at UT Southwestern Medical Center; and Ratna Vadlamudi, PhD, Professor at UT Health San Antonio.

In the current work, Ahn and his colleagues tested a novel stereospecific small molecule he synthesized called ERX-41, which targets the ER for its effects against BC cells. The research was performed on isolated cells, in human cancer tissue, as well as in human cancers grown in mice.

To investigate the ERX-41 molecule, the team utilized a variety of biochemical and ultrastructural studies. Cancer cells treated with ERX-41 revealed that the endoplasmic reticulum, an organelle that processes and folds proteins into their functional forms, was severely dilated in the treated cells. ERX-41 works by binding with lysosomal acid lipase A (LIPA), a protein found in the cell's endoplasmic reticulum. The pharmacologic inhibition of LIPA by ERX-41 dramatically enhances endoplasmic reticulum stress in cancer cells, shuts down de novo protein synthesis, blocks proliferation, and induces apoptosis without killing healthy cells in vitro. Additionally, ERX-41 not only killed ER-positive cancers in petri dishes, but also readily killed TNBCs, including more than 20 distinct TNBC cell lines. Of note, ERX-41 activity is independent of LIPA lipase function, but dependent on its endoplasmic reticulum localization.

Next, the team tested the molecule in mice with human forms of cancerous tumors. ERX-41 effectively shrunk human cancers and several of these cancer cell lines when grown as tumors. The research team also tested the compound in healthy mice and observed no discernible toxicity, such as weight fluctuation or behavioral changes. In addition, ERX-41 was also able to kill cancer cells in human tissue that were collected from patients who had recently had their tumors removed. Other experiments revealed that in addition to ER-positive BCs and TNBCs, ERX-41 is effective against other cancer types with elevated endoplasmic reticulum stress, including hard-to-treat pancreatic, glioblastoma, and ovarian cancers. Oncology Times reached out to Ahn, the co-corresponding author, for additional insights into the study.

Oncology Times: What are some of the current challenges when it comes to the targeted treatment of TNBC?

Ahn: “TNBC is characterized by high heterogeneity, high rates of metastasis, and poor prognosis. Current standard of care for TNBC is based on surgery and chemotherapy, which work initially but are almost useless in advanced stage. The heterogeneity of TNBC means that targeted therapies may only treat a subset of patients with advanced TNBC and may not have a durable response. There is an unmet need for an effective agent that targets the fundamental processes within these cancer cells.”

Oncology Times: What motivated you to pursue this research study? Can you discuss the approach of structure-based rational drug design and how it led to the synthesis of ERX-41?

Ahn: “I have been passionate on designing small molecules for inhibiting protein-protein interactions for my research. Unlike screening campaigns that many investigators and companies routinely do, I wanted to develop a rational structure-based design approach because it can make a broad impact on a number of target proteins once successfully accomplished. To that end, I designed novel molecular scaffolds based on oligo-benzamide structures and demonstrated their utility on several target proteins, including androgen and estrogen receptors in prostate and breast cancer cells, respectively. It was a surprising discovery that a series of compounds, including ERX-41, showed unexpected but remarkable growth inhibition on TNBC cells despite the absence of estrogen receptor.

“After many years of investigation identifying the new molecular target of ERX-41, we finally pinpointed it to LIPA that appears to be involved in inducing stress in endoplasmic reticulum and in turn cell death. Then, we found that LIPA is overexpressed in other tumor cells that have been difficult to be killed. Through the newly identified target, LIPA, ERX-41 demonstrates outstanding potency on breast, ovarian, and brain cancer cells.”

Oncology Times: What is the clinical significance of this study? Looking to the future, what are some potential applications and competitive advantages of this methodology?

Ahn: “This new targeted therapy exploits specific vulnerabilities in cancer cells that are not seen in normal cells. Our data indicate that ERX-41 targets a fundamental vulnerability in cancer cells, the high basal level of ER stress, and may be able to overcome the intertumoral and intratumoral heterogeneity of cancer. The safety profile and high therapeutic index of this compound are particularly notable and bode well for clinical translation. The ability of our drugs to induce endoplasmic reticulum stress in a variety of solid tumors may allow for broader application of our work across multiple cancer types.”

Oncology Times: What were some of the limitations of this study and are there any ongoing studies to address some of these limitations?

Ahn: “Our study showed very robust preclinical results. In order to move the drug forward to clinical trials, [researchers are] optimizing synthesis, formulation, and delivery routes and performing the studies necessary for FDA investigational new drug approval.”

Dibash Kumar Das is a contributing writer.

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
    Home  Clinical Resource Center
    Current Issue       Search OT
    Archives Get OT Enews
    Blogs Email us!