On September 12, 2022 Theratechnologies Inc. ("Theratechnologies" or the "Company") (TSX: TH) (NASDAQ: THTX), a biopharmaceutical company focused on the development and commercialization of innovative therapies, reported the publication of a preclinical study demonstrating the in vitro and in vivo efficacy of TH1902, an investigational sortilin (SORT1)-targeted peptide-drug conjugate, in inhibiting ovarian cancer and triple-negative breast cancer (TNBC) stem-like cells’ (CSCs) tumor growth (Press release, Theratechnologies, SEP 12, 2022, View Source [SID1234619434]). The study, published as part of the special issue of Pharmaceutics "Targeting Drug Resistance and Metastatic Pathways for Cancer Therapy", reports that TH1902 appears to exert anticancer activity that is superior to unconjugated docetaxel in preclinical models, in part by circumventing the chemoresistance phenotype that is often responsible for treatment failure and cancer recurrence.
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SORT1 is a scavenger receptor protein that binds to circulating proteins and peptides prior to their intracellular internalization. It is upregulated in several types of cancer. TH1902, now being investigated across at least eight solid tumor types in a Phase 1 clinical trial, has been shown in preclinical models to recognize and exploit SORT1 function, to efficiently trigger in vitro cell death through apoptosis, to inhibit in vitro cell cycling by trapping cells into the G2/M phase, and to inhibit in vivo growth of CSCs from gynecological cancers including ovarian cancer and TNBC. The Pharmaceutics paper provides the first evidence for TH1902 targeting of human breast and ovarian CSCs, both in vitro and in vivo. The limited ability of docetaxel, a widely used cancer chemotherapeutic agent, to inhibit the growth of CSCs from TNBC and ovarian cancer may be one mechanism of resistance and limit the effectiveness of the drug in controlling tumor growth and spread.
"The development of resistance to chemotherapy is a major obstacle to successful anticancer treatment, and the presence of cancer stem-like cells within tumors is believed to play an important role in that process," said Dr. Christian Marsolais, Chief Medical Officer, Theratechnologies. "The Pharmaceutics publication provides important insights into the ability of TH1902 to inhibit the growth of these cells."
In the Pharmaceutics paper, researchers at Theratechnologies and the Molecular Oncology Laboratory at Université du Québec à Montréal (UQAM) describe the activity of TH1902 against CSCs and its ability to circumvent some of the known resistance phenotypes associated with CSCs. Their findings suggest that TH1902 targets cancer cells overexpressing the sortilin receptor – an effect that is absent in healthy cells. Additionally, at doses equivalent to docetaxel, single-agent TH1902 exhibited superior efficacy against breast and ovarian CSCs, compared to docetaxel alone. Finally, when combined with carboplatin in an ovarian tumor model, the efficacy of TH1902 was also superior to that of paclitaxel- or docetaxel-carboplatin combinations. In TNBC and ovarian CSCs animal models, TH1902 decreased tumor growth by 80%, compared to roughly 35% in docetaxel-treated mouse models.
"Given our enhanced understanding of the association of SORT1 and cancer resistance to chemotherapy, using TH1902 to exploit SORT1 function within cancer stem-like cells may further offer a path to bypassing the chemoresistance phenotype often responsible for cancer recurrence," stated Dr. Borhane Annabi, Professor of Biochemistry and Chair in Cancer Prevention and Treatment at UQAM. "TH1902 thus appears to offer a promising strategy for targeting cancer cells that exhibit plasticity, metastatic potential, and resistance to chemotherapy."
The U.S. Food and Drug Administration (FDA) granted TH1902 Fast-Track Designation in February 2021. The basket portion of the Phase 1a/1b trial is currently enrolling at sites across the United States (TH1902 in Patients With Advanced Solid Tumors – Full Text View – ClinicalTrials.gov).
About TH1902 and SORT1+ Technology
Theratechnologies is currently developing a platform of proprietary peptides called SORT1+ TechnologyTM for cancer drug development targeting SORT1 receptors. The SORT1 receptor plays a significant role in protein internalization, sorting and trafficking. It is highly expressed in cancer cells compared to healthy tissue, which makes SORT1 an attractive target for cancer drug development. Expression of SORT1 is associated with aggressive disease, poor prognosis and decreased survival. It is estimated that the SORT1 receptor is expressed in 40% to 90% of cases of endometrial, ovarian, colorectal, triple-negative breast and pancreatic cancers.
TH1902 is currently Theratechnologies’ lead investigational peptide-drug conjugate (PDC) candidate for the treatment of cancer derived from its SORT1+ Technology. It is the company’s proprietary peptide linked to docetaxel – a commonly used cytotoxic agent used to treat many cancers. The FDA granted fast track designation to TH1902 as a single agent for the treatment of all sortilin-positive recurrent advanced solid tumors that are refractory to standard therapy.