A meshwork of membranous tunnels studded with protein and lipid manufacturing units crisscross the cytoplasm of all nucleated cells. In a range of cancers, including pancreatic, glioblastoma and ovarian cancers, accumulation of unfolded or misfolded proteins in this meshwork of tunnels, the endoplasmic reticulum (ER), leads to stress.

A preclinical study published on June 2, 2022, has uncovered a way of exploiting this vulnerability, using a new small, orally bioavailable, compound, ERX-41, that exacerbates ER stress, resulting in the death of a range of cancer types with already elevated ER stress.

These findings that could lead to new drugs to treat hard-to-treat cancers, are published in the Nature Cancer article “Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress.” The study is conducted on in vitro cultures of several types of cancer cells, and in mouse models with grafted human tumors (xenografts).

Ratna Vadlamudi, PhD, of The University of Texas Health Science Center at San Antonio, is co-senior author of the study [UT Health San Antonio.]
“We identified a critical vulnerability in multiple cancers and have validated our findings in multiple cancer cell types and animal models,” said Ratna Vadlamudi, PhD, professor of obstetrics and gynecology at the University of Texas Health Science Center at San Antonio, who is a co-senior author of the study. “The range of cell lines and xenografts in which the compound has been shown to work is compelling and indicates that it is targeting a fundamental vulnerability in cancer cells.”

In 2017, Vadlamudi’s lab identified a compound called ERX-11 that targets the estrogen receptor, a protein that drives most breast cancers. Screening for chemical analogs of ERX-11, the researchers identified ERX-41 that not only killed cancer cells bearing estrogen receptors but also killed triple-negative breast cancers (TNBCs) in over 20 different cell lines. TNBCs lack receptors for estrogen, progesterone, and human epidermal growth factor 2. This lack of therapeutic targets on TNBCs make them notoriously hard to treat.

As part of the current study, the researchers show ERX-41 is effective in killing many human tumors grown from several TNBC cell lines in mouse models. The compound is also effective in shrinking patient-derived breast tumors grown in mouse models, without affecting normal breast cells or inducing toxicity in the host animal model.

“The safety profile and high therapeutic index of this compound is particularly notable and bodes well for clinical translation,” said Vadlamudi.

In addition to estrogen receptor-positive breast cancers and TNBC, ERX-41 is also effective against other solid tumor types with elevated ER stress, such as cancers of the breast, brain, pancreas, and ovary.

The authors demonstrate ERX-41 binds an enzyme called lysosomal acid lipase A (LIPA) to induce ER stress and subsequent cell death. The authors provide evidence of target specificity by showing that specific LIPA mutations generate resistance to ERX-41 efficacy.

The study also shows that the anti-cancer activity of ERX-41 is independent of LIPA’s lipase activity but dependent on its location in the ER. The team reveals, when ERX-41 binds LIPA, it decreases the expression of several ER proteins involved in protein folding, which results in ER stress.

“Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death,” the authors conclude.

The candidate drug has been licensed to EtiraRx, a Dallas-based company that plans to move into clinical trials in early 2023. This work was funded by grants from the National Institutes of Health and National Cancer Institute.

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