Theratechnologies Inc. announced 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. 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. 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. 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.