August 27, 2020
A new type of breast cancer drug developed by researchers at the University of Illinois Chicago can help halt progression of disease and is not toxic, according to phase 1 clinical trials. The drug is specifically designed for women whose cancer has stopped responding to hormone therapy.
The results are published in the journal Breast Cancer Research and Treatment.
Breast cancer affects one in eight women in the United States, and while there are many types of breast cancer, around 80% are categorized as estrogen receptor-positive, or ER-positive. This means the cancer cells have receptors — molecules that can receive signals from chemicals in the body — that are sensitive to and react to the hormone estrogen.
In the case of ER-positive breast cancer, this means that estrogen fuels cancer growth. To treat this type of breast cancer, doctors prescribe medication to block hormone production in the body or interfere with the effect hormones have on cancer cells. This type of treatment is called hormone therapy. However, nearly half of women treated with hormone therapy become resistant, leaving traditional chemotherapy and its side effects as the only option for treatment.
“While there are many treatments for breast cancer, about half of women with ER-positive cancers become resistant to hormone therapy, leaving them with few treatments other than chemotherapy, with its well-known toxic side effects,” said Debra Tonetti, professor of pharmacology at the UIC College of Pharmacy and an author on the paper.
Tonetti, together with Gregory Thatcher, the Hans W. Vahlteich Chair of medicinal chemistry at UIC and co-author on the paper, developed the new drug, called TTC-352. Preclinical studies showed that TTC-352, which is a selective human estrogen receptor partial agonist, causes complete tumor regression, but unlike tamoxifen, may pose a reduced risk of uterine cancer development.
In the phase 1 clinical trial, 15 women who had metastatic breast cancer and previously were treated with several rounds of hormone therapy and, in some cases, chemotherapy including a CDK4/6 inhibitor, were enrolled. The researchers found that there were no toxic side effects, even at the highest doses.
In total, six patients experienced stable disease with a lack of disease progression: two for 6 months and four for 3 months.
“This is very encouraging because these participants were at an advanced stage of their disease, and we saw that their cancers stopped growing for a significant amount of time,” said Tonetti, who is also a member of the University of Illinois Cancer Center.
The doses given to participants were in line with what the researchers believe are therapeutic levels — in other words, participants received doses equivalent with what patients would be given to treat their disease.
“The results of the phase 1 trial indicate that TTC-352 is a safe and tolerable alternative to chemotherapy — therefore, without the side effects of chemotherapy — for patients who have already been treated with hormone therapy,” Thatcher said.
Participants were enrolled at Regions Cancer Care Center, HealthPartners Institute, St. Paul, Minnesota; HonorHealth Research Institute, Scottsdale, Arizona; Sanford Health, Sioux Falls, South Dakota, and the University of Wisconsin, Madison.
TTC-352 was approved as an Investigational New Drug by the U.S Food and Drug Administration in 2017. UIC has licensed the drug to TTC Oncology, LLC., which funded the study, for human clinical trials.
Li Liu, James Fischer and Elizabeth Wiley of UIC; Dr. Arkadiusz Dudek and Dr. Randolph Hurley of Health Partners Institute; Robert Venuti of TTC Oncology, Dr. Ruth O’Regan of the University of Wisconsin are co-authors on the paper.
July 10, 2018
So far, First time's a charm for Tonetti's initial clinical trial
Debra Tonetti’s first clinical trial has not gone the way she anticipated. It’s gone much better.
Tonetti, PhD, a University of Illinois Cancer Center member, associate professor of pharmacology and interim head of the department of biopharmaceutical sciences, is testing a drug she helped developed with fellow UI Cancer Center member Greg Thatcher that has the potential to help women whose breast cancer has stopped responding to hormone therapy.
Patient recruitment into the Phase 1 trial of the new drug, TTC-352, has proceeded more rapidly than anticipated. The drug is a selective estrogen mimic that causes complete tumor regression, but unlike tamoxifen, it may pose a reduced risk of uterine cancer development. The trial is currently open at four sites throughout the U.S., with the University of Illinois Hospital & Health Sciences System being a fifth and final location beginning in the coming months.
About two out of three breast cancers are hormone receptor-positive, whose cells have receptors (proteins) that attach to the hormone estrogen (ER-positive cancers) and/or progesterone (PR-positive cancers). For these cancers, high estrogen levels help the cancer cells grow and spread.
Hormone therapy is considered to be highly effective at fighting estrogen receptor-positive breast cancer, but nearly 50 percent of the women who undergo this type of treatment still develop a resistance to the medication and experience a recurrence, Tonetti said. TTC-352, a selective human estrogen receptor partial agonist (ShERPA), may be as effective at treating breast cancer as other hormone therapy drugs, like tamoxifen or aromatase inhibitors, but with fewer side effects.
The Phase 1 trial will determine the maximum tolerated oral dose of TTC-352 in patients with metastatic breast cancer that has progressed despite endocrine therapy. It will also evaluate the patients’ best response to treatment; the duration of progression-free survival, as well as overall survival; the safety profile of the drug; and the drug’s pharmacokinetic profile. It will also study the association between tumor response to the drug and its expression of a specific predictive biomarker, protein kinase C alpha, or PKC alpha, Tonetti said.
“We have observed that breast cancers that develop a resistance to hormone therapy have elevated PKC alpha expression,” she said. “Our previous studies suggest that PKC alpha may predict a positive response to estrogen mimics like TTC-352.”
Phase 1 trials test for a drug’s safety, but hints of efficacy can also be observed. With initial results appearing to be promising, Tonetti said a new problem has arisen.
“The trial calls for testing five dosing levels for safety,” Tonetti said. “Now we have all these patients that are presumably going to do well and you can’t just take the drug away from them. Now we need to manufacture more of the drug.
“It may very well be that our Phase 1 trial will be finished with fewer patients and at a faster rate. This means we will be positioned well for beginning a Phase 2 trial.”
Tonetti and Thatcher, who serves as co-director of the UI Cancer Center’s Translational and Clinical Oncology Program, have also collaborated on a new orally bioavailable selective estrogen receptor downregulator (SERD) that has been licensed to G1 Therapeutics, a North Carolina-based biopharmaceutical company. The company plans to combine the SERD with G1’s cyclin dependent kinase (CDK) 4/6 inhibitor to treat estrogen receptor positive and HER2 negative breast cancer.
“Presently there is only one FDA-approved SERD on the market,” Tonetti said. “When it comes to endocrine therapy there are few options. We believe this new drug is promising as well.”
Tonetti, who co-founded the biopharmaceutical company TTC Oncology LLC with Thatcher in 2016 to produce the drug TTC-352, became interested in studying cancer while serving a postdoctoral fellowship at Argonne National Laboratory, working with the PKC signaling pathway conducting research on differentiation mechanisms in promyelocytic leukemia. She then trained under V. Craig Jordan, known as the “Father of Tamoxifen”, at Northwestern University before coming to UIC in 2001. Her research has been funded by the National Institutes of Health, the Chicago Biomedical Consortium, the Avon Foundation, and the Susan G. Komen Breast Cancer Foundation, among other organizations.
Although the Phase 1 trial on TTC-352 is not yet complete, 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 successful treatment of patients in the future,” she said.
March 21, 2018
UIC breast cancer drug in first human clinical trial
A University of Illinois at Chicago-developed breast cancer drug that has the potential to help women whose cancer has stopped responding to hormone therapy recently entered its first human clinical trial.
Breast cancer affects one in eight women in the United States, and while there are many types of breast cancer, around 80 percent are categorized as estrogen receptor-positive, or ER-positive. This means the cancer cells have receptors – molecules that can receive signals from chemicals in the body – that are sensitive to and react to the hormone estrogen.
In the case of ER-positive breast cancer, this means that estrogen fuels cancer growth. To treat this type of breast cancer, doctors prescribe medication to block hormone production in the body or interfere with the effect hormones have on cancer cells. This type of treatment is called hormone therapy.
“Hormone therapy is considered to be highly effective at fighting estrogen receptor-positive breast cancer, but nearly half of all women who undergo this type of treatment still develop a resistance to the medication and experience a recurrence,” said Debra Tonetti, associate professor of pharmacology and head of biopharmaceutical sciences in the UIC College of Pharmacy.
Tonetti, who is one of the developers of the new drug, called TTC-352, says the drug may be just as effective at treating breast cancer as other hormone therapy drugs, like tamoxifen or aromatase inhibitors, but with fewer side effects.
To develop the drug, Tonetti worked with Greg Thatcher, professor of medicinal chemistry and pharmacognosy. Together, they tested the drug first in the lab, then in animals.
“Preclinical studies have shown that TTC-352, which is a selective estrogen mimic, causes complete tumor regression, but unlike tamoxifen, may pose a reduced risk of uterine cancer development,” Tonetti said.
Thatcher added that because TTC-352 is a selective estrogen mimic, “its mechanism is different than that of tamoxifen and aromatase inhibitors, and it has been shown to work on cancers that have grown resistant to these standard-of-care drugs.”
In July 2017, the U.S. Food and Drug Administration approved the drug, which UIC has licensed to TTC Oncology, LLC, for trial in humans.
The Phase I human trial will determine the maximum tolerated oral dose of TTC-352 in patients with metastatic breast cancer that has progressed despite endocrine therapy. It will also evaluate patient best response to treatment, duration of progression-free survival, duration of overall survival, the safety profile of the drug and the drug’s pharmacokinetic profile. The study will also investigate the association between tumor response to the drug and its expression of a specific predictive biomarker: protein kinase C alpha, or PKC alpha.
“We have observed that breast cancers that develop a resistance to hormone therapy have elevated PKC alpha expression and our previous studies suggest that PKC alpha may predict a positive response to estrogen mimics like TTC-352,” Tonetti said.
Tonetti says if the trial results are positive and if patients’ response to the drug is correlated with PKC alpha expression, TTC-352 has the potential to become a first line therapeutic drug for patients with estrogen receptor-positive breast cancer that expresses the biomarker.
The trial is now open at two sites: Regions Cancer Center in St. Paul, Minnesota, and the Virginia G. Piper Cancer Center in Scottsdale, Arizona. UIC will analyze the tumors for the PKC alpha biomarker.
TTC Oncology funds the study.
November 8, 2016
Innovator of the Year mixes science, business
Greg Thatcher, innovator of the year
Each year, the Office of Technology Management celebrates UIC faculty inventors. The Innovator of the Year Award recognizes researchers who have advanced their inventions toward commercialization. The Inventor of the Year Award honors researchers whose discoveries have the potential for significant impact. The awards include a $3,500 prize and a plaque, which is prominently displayed in the hallway of the UIC Office of Technology Management.
Alzheimer’s disease, neurodegenerative disorders, cancer, sleep-disordered breathing. The illnesses may seem dissimilar but they have one commonality: Greg Thatcher is working to find a cure for them all.
Throughout his career, Thatcher has melded his expertise in academia and science with business. His numerous patents have led to the launch of several start-up companies whose goal is to bring drug candidates to clinical trials.
Innovation does not just come from time and effort, Thatcher said, but also money.
“Venture capital financiers will tell you that ideas are 10-a-penny. In drug discovery, it will take $5 million to $10 million and two years to take an idea from bench to a signal that the drug has any effect in humans, and the cumulative risk of failure is over 90 percent,” said Thatcher, Hans Vahlteich Endowed Chair of Medicinal Chemistry in the College of Pharmacy.
“But for an idea to have value, we must try to move the idea beyond the academic setting to become a translational technology that can potentially provide real benefit to society at large and relieve the suffering of disease, even if the risk and effort is very high.”
A prolific scientist, Thatcher’s expertise bridges chemistry and biology, and includes nitric oxide chemical biology, oxidative stress, protein covalent modification, and estrogen receptor modulation focusing on Alzheimer’s disease and breast cancer. He has been involved in several start-up companies, the latest, TTC Oncology, with Debra Tonetti, associate professor of pharmacology.
The new company licenses agents for therapy of treatment-resistant breast cancer and an alternate family of agents for breast cancer that have also been out-licensed. He also has several Alzheimer’s disease technologies currently licensed to biotechnology companies. Both approaches to treating breast cancer were pioneered by a graduate student, Rui Xiong, proving Thatcher’s mantra that smart, young trainees drive innovation.
Thatcher is also the founding director of a campus-wide center for drug discovery. The UICentre engages biomedical researchers in collaborative teams to translate ideas and inventions to small molecule, proprietary lead compounds for further drug research and development.
A faculty member since 2003, Thatcher has supervised or co-supervised more than 45 graduate trainees and has been involved in pre- and postdoctoral training and education, mentoring trainees who have proceeded to leadership positions in the pharmaceutical industry, bioventures and academia.
In addition to being named Innovator of the Year, Thatcher has also been named UIC Graduate Mentor of the Year and a University Scholar.
Thatcher is currently principal investigator or co-investigator on nine active grants, funded by either the National Institutes of Health, private industry, or the Chicago Biomedical Consortium.
Jerry Bauman, dean of the College of Pharmacy, said Thatcher’s work is “truly translational.”
“It is extremely clear that Greg is an innovator, and I can think of no one more deserving of this award,” Bauman said. “We are proud to have him at UIC and in our college.”
Greg Thatcher mixes science with business.
(Photo: Roberta Dupuis-Devlin)
Debra Tonetti - Greg Thatcher