Bayer’s drug, which toxicizes cancer protection pathways, eradicates breast tumors in mice

Bayer, a clinical trial breast cancer drug recently approved by Systems Oncology, showed a strong antitumor response in mice, providing early clues as to why a German pharmaceutical company invested $ 25 million in preclinical assets last September. Provided.

The drug, called ErSO, usually works by overactivating the pathways that protect the tumor and making it toxic to cancer cells. Eradicated both primary and metastatic tumors in a mouse model of estrogen receptor-positive breast cancer, according to the results published in. Scientific translation medicine..

The pathway targeted by ErSO is called the predictive endoplasmic reticulum stress response (aUPR). Through mild and transient activation, aUPR prepares ER-positive cancer cells to grow and protects them from stress such as anti-cancer treatments.

But, PNAS In the 2015 study, Professors of Biochemistry, David Shapiro, Ph.D. A research team at the University of Illinois at Urbana-Champaign, led by the drug, showed that large-scale, sustained activation of aUPR by drugs could instead inhibit protein synthesis and deprive ER-positive breasts of cancer. Cells are an important component of survival.

For a new study, Shapiro et al. Identified ErSO as a more potent aUPR hyperactivator capable of selectively killing ER-positive breast cancer cells.

Related: ASCO: Sanofi says early amcenestrant data can be seen as “endocrine backbone therapy” for breast cancer

In multiple mouse models of ER-positive breast cancer, ErSO rapidly killed large numbers of tumor cells just days after treatment. Combining data from four mouse models, the team reported that 38 of 39 tumors regressed by more than 95% and about half of the cases were reduced to undetectable levels. The team found that even tumors that completely disappeared and did not re-grow after discontinuation of treatment remained completely sensitive to another cycle of ErSO.

In another mouse model with variants, patient-derived breast tumors with low ER expression, oral ErSO treatment, standard treatments tamoxifen and AstraZeneca fasrodex (fulvestrant) in blocking tumor growth. ) Was exceeded.

“Many of these breast cancers shrink by more than 99% in just three days,” says Shapiro. Said In the statement. “ErSO has a fast-acting effect and its effect on breast cancer in mice is significant and dramatic.”

In addition, Bayer’s drugs also significantly reduced cancer metastasis in multiple locations, including the lungs, bones, and brain, the researchers said.

Related: AstraZeneca Stops Breast and Prostate Cancer Programs In Fourth Quarter Pipeline Culling

The success of Faslodex has led some biopharmacy companies to develop next-generation selective ER down regulators (SERDs). They include Sanofi. Move The drug, amcenestrant, moved to phase 3 trials for tamoxifen after showing promising early results in combination with Pfizer’s CDK4 / 6 inhibitor, Ibrance.

Roche is pairing the SERD drug giledestrant with Ibrance in Phase 3. persevERA trial. And Radius Health is working with Menarini to develop a SERD dubbed oral elacestrant.It expects Phase 3 data from Emerald Trial later this year.

The UIUC team noted that in mouse models, second-generation SERDs usually induced moderate regression of the primary tumor. Those tested for metastases have shown limited efficacy. And resistance is still a risk of CDK4 / 6 inhibitors.

Compared to the general mode of inhibitory action on ER, ErSO may provide a “turn-on approach to transform tumor-selective protective pathways into deadly targeted anti-cancer responses,” researchers say. I am writing in my research. The ability of drugs to target metastatic tumors and their activity in ER hypotumors, traditionally considered ER-negative, may widen their potential therapeutic range, the researchers said.

Bayer picked up Global rights to ErSO in September are $ 25 million in advance and Systems Oncology is eligible to receive milestone payments of up to $ 345 million.

The current study found that the drug was well tolerated in mice and dogs, but the UIUC team said further safety analysis was needed before testing in humans. Researchers are also planning to investigate the use of ErSO for other types of ER-positive cancers. Bayer’s drug, which toxicizes cancer protection pathways, eradicates breast tumors in mice

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