Angiogenesis Inhibitors in Personalized Combination Regimens for the Treatment of Advanced Refractory Cancers

Abstract

Background Angiogenic factors are commonly activated in solid tumors and present a viable therapeutic target. However, anticancer treatment with angiogenesis inhibitors (AGI) is limited to a few cancers, mostly as monotherapy and not selected based on molecular indications. We aimed to determine whether patient-specific combination regimens with AGI and other anticancer agents when selected based on multi-analyte tumor interrogation (ETA: Encyclopedic Tumor Analysis) can expand the scope of AGIs in advanced refractory solid organ cancers with improved treatment responses. Methods We evaluated treatment outcomes in 60 patients with advanced, refractory solid organ cancers who received ETA-guided combination regimens of AGI with other targeted, endocrine or cytotoxic agents. Radiological evaluation of treatment response was followed by determination of Objective Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and Overall Survival (OS). Results Among the 60 patients, Partial Response (PR) was observed in 28 cases (46.7%), Stable Disease (SD) was observed in 29 cases (48.3%) and Disease Progression (PD, within 60 days) was observed in 3 cases (5.0%). The ORR was 46.7% and DCR was 95.0%. At the most recent follow, up the median PFS (mPFS) was 5.0 months and median OS (mOS) was 8.9 months. There were no Grade 4 therapy related adverse events or treatment related deaths. Conclusions ETA-guided patient-specific combination regimens with AGI and other anti-neoplastic agents, can yield improved outcomes over AGI monotherapy. Trial Registration Details of all trials are available at WHO-ICTRP: https://apps.who.int/trialsearch/. RESILIENT ID CTRI/2018/02/011808. LIQUID IMPACT ID CTRI/2019/02/017548.

Molecular targeted therapy for anticancer treatment

“…Inhibitors targeting PDGFR, VEGFR, or FGFR family receptors and Ret: Tumor angiogenesis is a hallmark of cancer. Several growth factors and their receptors, such as platelet-derived growth factor (PDGF)/PDGFR, vascular endothelial growth factor (VEGF)/VEGFR, fibroblast growth factor (FGF)/FGFR, stem cell factor (SCF)/c-Kit, glial cell line-derived neurotrophic factor (GDNF)-family ligands/ rearranged during transfection (RET), and angiopoietin/Tie 22,111 , regulate the growth, differentiation and migration of cancer cells and angiogenic activities of vascular endothelial cells 22,111 . PDGFs are members of the 'cysteine knot' growth factor superfamily, the members of which contain at least three disulfide bridges and forms homo-or heterodimers 112 .…”