that are sensitive to IGFR inhibitors rapidly upregulate signaling through the EGFR system as a means to resistance 38 , and the converse is also true 37 . For this reason, combining agents targeting both of these pathways would seem a rational approach likely to enhance effectiveness of the agents. The interaction of the IGF and EGF signaling Itraconazole pathways has been demonstrated in multiple preclinical systems, and therapeutic cooperativity has been confirmed, HORM CANC (0) :385 – 39 regardless of whether antibodies or small molecule TKIs have been used 5 , 36 , 37 , 39 , 40 . Recently a clinical trial of the IGFR-targeting OSI-906 and the EGFR-targeting erlotinib (originally OSI-774) is already underway.
Phase I studies have shown that there is moderate but manageable toxicity of the Abiraterone combination therapy, and an expansion cohort using nonsmall cell lung cancer (NSCLC) patients was planned along with an upcoming phase II effort. This study indicates the feasibility of combination therapy and should lead to new and exciting trials in this area. Other combinations that may be worthy of consideration would be joint IGFR/FGFR blockade. Using TKIs in Novel Treatment Paradigms Antiangiogenic Agents Since the groundbreaking work of Folkman 4 , there has been recognition that tumors require the development of new vessels and that this requirement presents a therapeutic opportunity 4 . Angiogenesis is driven primarily by signaling through the vascular epithelial growth factor (VEGF) pathway, and there are three VEGF receptors, VEGFR (Flt), VEGFR (Flk/KDR), and VEGFR3 (Flt4). VEGFR is thought to be the major mediator of blood vessel growth, although the others may also play roles.
There is good in vivo evidence in model systems that targeting the vasculature is effective, including the obser- vation that pretreatment with anti-VE-cadherin-linked agents to “ normalize ” the tumor vascular enhances subse- quent delivery of cytotoxic chemotherapy 43 . The first antiangiogenic therapy to be approved was the monoclonal antibody ZD-1839 184475-35-2 bevacizumab, which targets the VEGFR. Initial studies demonstrated modest effectiveness against colon cancer 44 , and it was subsequently approved for treatment of NSCLC and breast cancer as well 45 . Recent data have shed some doubt on the usefulness of the agent for breast cancer, and a reevaluation of this therapy is currently underway 46 . More recent agents that target the VEGFRs include the multikinase inhibitors sorafenib and sunitinib, which target these pathways among others. A trial of sunitinib as a single agent for ACC was not successful, although the trial was confounded by the fact that adequate serum levels of the drug were rarely obtained 47 .
A second signaling system that seems to be important for angiogeneisis involves MET (hepatocyte growth factor) and its receptor HGFR. MET is typically expressed at high levels in the tumor microenvironment, and this signaling system appears to be an buy ZD-1839 important secondary pathway for angiogenesis. A switch to MET-HGFR may be an impor- tant mechanism that accounts for resistance of tumors to therapies targeted to the VEGFRs, such that combination therapy has been shown to be effective in preclinical 4 HORM CANC (0) :385 – 39 models 48 . Intriguingly, XL-84, a multikinase inhibitor currently in clinical trials, targets both VEGFR and HGF, making it an agent with potential promise in this area. Antimetastasis Agents Because metastatic disease is a common cause of morbidity and mortality in ACC, the emerging field of metastasis suppression may be health care highly relevant to the therapy of ACC tumors. Although a thorough review is the beyond the scope of this paper, many excellent reviews on this topic have been published 49 – 5 . In terms of therapeutic interventions, an intriguing target is stromal-derived factor (SDF, also known as CXCL) and its receptor CXCR4. SDF is a secreted cytokine whose levels are increased by mutant forms of p53 53 such as may be observed in ACC tumors 5