Second Thatcher, Tonetti collaboration entering clinical trial

There is currently no oral selective estrogen receptor degrader (SERD) on the market today to treat breast cancer. University of Illinois Cancer Center members Greg Thatcher and Debra Tonetti believe they’ve developed a product that will change that.

G1T48, licensed to Durham, N.C.-based biopharmaceutical company G1 Therapeutics, has entered into Phase 1/2a clinical trial. The drug was demonstrated to be more potent in preclinical trials to fulvestrant – the only SERD approved by the U.S. Food and Drug Administration to treat hormone receptor positive metastatic breast cancer in postmenopausal women, according to representatives at G1 Therapeutics.

About 70 percent of breast cancer patients have estrogen receptor positive (ER+) tumors, said Tonetti, PhD, professor of pharmacology and interim department head of biopharmaceutical sciences in the UIC College of Pharmacy. Tamoxifen and aromatase inhibitors – both of which are considered endocrine or hormone therapy – represent first-line treatment for ER+ patients. However, up to 50 percent of these patients either do not respond to the treatment or acquire resistance within five years of therapy, she said.

G1 Therapeutics had been interested in licensing a SERD drug but had not found one that they thought would succeed. But after reviewing the pre-clinical data for G1T48, the company believed it was the one, Thatcher said.

“Compared to pharmaceutical companies, resources in academia are quite limited. Therefore, a new niche must be uncovered, and we feel G1T48 may be the first in its class, and the best in its class,” said Thatcher, Hans W. Vahlteich Chair of Medicinal Chemistry and co-director of the UI Cancer Center’s Translational and Oncology Program. “We believe patients will better tolerate and respond to G1T48 since it’s a once-daily oral medication.”

Fulvestrant was approved by the U.S. Food and Drug Administration in 2002, making it the first and only SERD on the market. It blocks and causes degradation of estrogen receptors and is used to treat metastatic breast cancer, most often after other hormone drugs (like tamoxifen or an aromatase inhibitor) have stopped working. It is given by injections into the buttocks. For the first month the shots are given two weeks apart. After that, they are given once a month. Fulvestrant is currently approved only for use in post-menopausal women.

There is strong scientific rationale and clinical validation supporting the combination of a SERD with a CDK4/6 inhibitor, such as palbociclib. G1 Therapeutics is interested in using G1T48 in combination with their own CDK4/6 inhibitor, lerociclib, for the treatment of patients with ER+, HER2- breast cancer, G1 Therapeutics stated.

This has been a busy, and successful, year for Thatcher and Tonetti, as G1T48 is the second drug they’ve developed to enter clinical trials. TTC-352 is a selective estrogen mimic that causes complete tumor regression, but unlike tamoxifen, it may pose a reduced risk of uterine cancer development. The drug, which is being tested at four sites throughout the U.S., with a fifth trial soon to be opened at the University of Illinois Hospital & Health Sciences System, is a selective human estrogen receptor partial agonist (ShERPA).

The Phase 1 trial on TTC-352 is nearing completion and Tonetti is optimistic that the drug will one day be a viable option to treat patients with breast cancer.  “We’re encouraged by the initial findings, and we’re optimistic about the future successful treatment of patients,” she said.

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