BBB & CCBIO seminar: Robert S. Kerbel
Antiangiogenic therapeutics in oncology: Overview, update, and future directions
Robert S. Kerbel
Biological Sciences Platform, Sunnybrook Research Institute, Toronto, and Department of Medical Biophysics, University of Toronto, Canada
One of the major advances in medical oncology drug development over the last decade has been the approval of nine different antiangiogenic drugs for over ten different cancer indications. The drugs include bevacizumab, the VEGF antibody, ramucirumab, the VEGFR-2 antibody, aflibercept, a VEGF decoy/trap protein, and a number of oral small molecule tyrosine kinase inhibitors (TKIs), including sunitinib, sorafenib, pazopanib, axitinib, regorafenib and nintedanib, which target VEGF receptors, among several other receptor tyrosine kinases. Among the major cancer types now treated with such drugs include colorectal, breast, ovarian, cervical, liver, gastric, renal cell and non small cell lung carcinomas, as well as soft tissue sarcomas and glioblastoma. However, the successes of the phase III clinical trials that led to these approvals have to be balanced with the incremental survival benefits gained, as well as some failures, the most notable of which are multiple phase III trials involving adjuvant treatment of early stage disease, and numerous phase III trials of various antiangiogenic TKIs plus standard chemotherapy in the metastatic treatment setting. Thus, similar to other targeted therapies, many strategies are being explored to improve the efficacy of antiangiogenic drug based therapies. These will be summarized, and include the following: 1) discovery of predictive biomarkers of future clinical benefit; 2) using longer duration therapy, particularly as ‘maintenance’ treatments; 3) defining mechanisms of innate and acquired resistance; 4) developing optimal chemotherapy backbone partners which may include ‘metronomic’ chemotherapy dosing regimens, especially for maintenance therapy; 5) developing improved (that is, more translationally relevant) preclinical models for investigational therapeutics; 6) assessing new angiogenic targets beyond VEGF, e.g. angiopoietin-2; 7) assessing combinations with other promising but different targeted therapies such as immunotherapy, e.g. using immune checkpoint control antibodies where there is a scientific rationale for doing so, e.g. neutralizing the local immunosuppressive effects caused by VEGF within the tumor microenvironment. Particular emphasis will be placed on discussion of personal studies regarding the development of new preclinical therapy models in mice involving postsurgical treatment of either early stage or late stage, advanced metastatic disease to evaluate antiangiogenic drug mechanisms and efficacy. Studies using these models have helped contribute to the clinical advancement of low-dose ‘metronomic’ chemotherapy, and the realization of “vessel co-option” as a possible major factor in explaining resistance or limited efficacy of antiangiogenic monotherapy for treatment of either early or late stage metastatic disease.
Chairperson: Oleg Tsinkalovsky, Department of Biomedicine