The long and winding road for the development of tasquinimod as an oral second-generation quinoline-3-carboxamide antiangiogenic drug for the treatment of prostate cancer

Abstract

Importance of the field Prostate cancer is the mostly commonly diagnosed non-skin cancer in males. The culmination of the last 70 years of clinical drug development has documented that androgen ablation plus taxane-based systemic chemotherapy enhances survival, but is not curative, in metastatic prostate cancer. To effect curative therapy, additional drugs must be developed that enhance the response when combined with androgen ablation/taxane therapy. Areas covered in this review The history of the discovery and development of tasquinimod as a second-generation oral quinoline-3-carboxamide analogue for prostate cancer will be presented. What the reader will gain The mechanism for such anticancer efficacy is via tasquinimod’s ability to inhibit the ‘angiogenic switch’ within cancer sites required for their continuous lethal growth. Take home message Tasquinimod is a novel inhibitor of tumor angiogenesis that enhances the therapeutic anticancer response when combined with other standard-of-care modalities (radiation, androgen ablation, and/or taxane-based chemotherapies) in experimental animal models, but does not inhibit normal wound healing. It has successfully completed clinical Phase II testing in humans and will shortly enter registration Phase III evaluation for the treatment of metastatic prostate cancer.

Anti-cancer potency of tasquinimod is enhanced via albumin-binding facilitating increased uptake in the tumor microenvironment

“…Tasquinimod's anti-cancer efficacy involves its inhibition of the reciprocal survival signaling pathways between the cancer cells and tumor infiltrating host cells suppressing the angiogenic switch needed for continued malignant growth in the compromised tumor microenvironment [9- 12]. Tasquinimod is currently in clinical development for the treatment of prostate cancer and other solid malignancies [13, 14]. In a placebo-controlled, phase II randomized trial, tasquinimod doubled median progression-free survival and prolonged survival of patients with metastatic, castrate resistant prostate cancer [15, 16].…”

Phase II Randomized, Double-Blind, Placebo-Controlled Study of Tasquinimod in Men With Minimally Symptomatic Metastatic Castrate-Resistant Prostate Cancer

“…Tasquinimod (TASQ) is an oral quinoline-3-carboxamide derivative with antiangiogenic properties [5][6][7] and tumor growth-inhibiting activity against human prostate cancer models, 5,6 possibly mediated through induction of the endogenous angiogenesis inhibitor thrombospondin-1. 8 A molecular target for TASQ is S100A9 (MRP-14), an immunomodulatory protein expressed on myeloid-derived suppressor cells (MDSCs), 9 which are present in the tumor microenvironment and stimulate angiogenesis using both vascular endothelial growth factor (VEGF) -dependent and VEGF-independent mechanisms.…”

Immunotherapy advances in uro-genital malignancies

“…Tasquinimod is a quinoline-3-carboxamide analog, a small molecular oral inhibitor of S100A9, a key cell surface regulator of MDSC function; it has shown anti-angiogenic, antitumor and immune-modulatory properties in preclinical models of prostate cancer and other solid tumors (Isaacs, 2010). In a randomized, double-blind, placebo-controlled phase II trial of men assigned to either oral once-daily tasquinimod 0.25 mg/die escalating to 1.0 mg/die over 4 weeks or placebo, median PFS was 7.6 versus 3.3 months (P = 0.0042) and tasquinimod showed an acceptable toxicity profile (Pili et al, 2011).…”