Targeting CX3CR1 to Counteract Metastatic Reseeding and Progression
Abstract
Despite the widespread mammogram screening and dramatic improvements in the surgical, radio-therapeutic, and chemotherapeutic approaches for the treatment of primary breast adenocarcinoma, the metastatic form of this tumor is still incurable. Breast cancer disseminates with high propensity to skeleton, liver, lungs, and brain, and these secondary lesions are extremely difficult to eradicate. At the onset of metastatic disease, which is first detected in the skeleton in more than 50% of cases, patients are very often asymptomatic. However, these initial tumors in the bone are rapidly followed by additional foci being detected both in the skeleton and soft tissue organs. It is now recognized that the circulating tumor cells (CTCs) detected with very high frequency in metastatic patients are shed by existing metastatic tumors and capable of re-seeding additional metastatic foci that eventually cause patients demise. Pharmacological approaches capable of halting or significantly decelerating the seeding of additional metastases from initial lesions have the potential to arrest the patients in an oligometastatic state. This would achieve two major objectives: (a) maintaining tumor burden at acceptable levels and (b) allowing combination treatments targeting CTCs in the blood, preventing the emergence of new lesions and therefore avoiding to "chase" the clinical progression of the disease. Our proposal intends to address this issue by developing novel pharmacological compounds to block the lodging of CTCs to the skeleton and avoid the rapid progression of the metastatic disease into its incurable stage. We have synthesized a series of novel compounds, and an issued patent application covering this series has recently published (Issued US patent no.: 8,435,993). We have also successfully validated our lead compound in the preclinical setting. Our drug discovery program was recently selected by the NExT Program at the National Cancer Institute (NCI) to receive support for Lead Optimization. This crucial infusion of technical resources will aid our medicinal chemistry efforts, with full commitment from the NCI to ensure that the new small-molecule antagonists we are developing enter human clinical trials in a timely manner. We are here seeking funding in support of our preclinical functional validation efforts. Since CTCs can survive a very short period of time in the blood, blocking their lodging to the skeleton with our novel compounds will dramatically increase the probabilities of their demise. Thus, in addition to counteracting the progression of metastatic disease, we aim to produce tumor-killing results, without exerting a direct cytotoxic effect on cancer cells. From a drug-safety perspective, this approach is invaluable. Importantly, several studies have shown that animals knocked down for the molecular target of our compounds are fully viable, indicating that the drugs we are developing are unlikely to cause toxicity. In conclusion, the overarching goal of this project is to synthesize drug-like candidates for an Investigational New Drug (IND) application to be filed before or by the end of the funding period. Based on the efficacy demonstrated in the preclinical setting, safety of the approach proposed and the implementation plan as conceived, the novel compounds that will be synthesized have an exceptional potential to be rapidly translated into safe and effective therapeutics for patients with metastatic breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1610038
Entities
People
- Alessandro Fatatis
Organizations
- Drexel University
- United States Army