Knowledge of the molecular events that contribute to prostate cancer progression has created opportunities to develop novel therapy strategies. It is now well established that c-Src, a non-receptor tyrosine kinase, regulates a complex signaling network that drives the development of castrate-resistance and bone metastases, events that signal the lethal phenotype of advanced disease. Preclinical studies have established a role for c-Src and Src Family Kinases (SFKs) in proliferation, angiogenesis, invasion and bone metabolism, thus implicating Src signaling in both epithelial and stromal mechanisms of disease progression. A number of small molecule inhibitors of SFK now exist, many of which have demonstrated efficacy in preclinical models and several that have been tested in patients with metastatic castrate-resistant prostate cancer. These agents have demonstrated provocative clinic activity, particularly in modulating the bone microenvironment in a therapeutically favorable manner. Here, we review the discovery and basic biology of c-Src and further discuss the role of SFK inhibitors in the treatment of advanced prostate cancer.

Purpose Liquid biopsies allow the tracking of clonal dynamics and detection of mutations during treatment. Experimental design We evaluated under blinded conditions the ability of cell free DNA (cfDNA) to detect RAS/BRAF mutations in the plasma of 42 metastatic colorectal cancer patients treated on a phase Ib/II trial of FOLFOX and dasatinib, with or without cetuximab. Results Prior to treatment, sequencing of archival tissue detected mutations in 25/42 patients (60%), while the cfDNA assay detected mutations in 37/42 patients (88%). Our cfDNA assay detected mutations with allele frequencies as low as 0.01%. After exposure to treatment, 41/42 patients (98%) had a cfDNA detected RAS/BRAF mutation. Of 21 patients followed with serial measurements who were RAS/BRAF mutant at baseline, 11 (52%) showed additional point mutation following treatment and 3 (14%) no longer had detectable levels of another mutant allele. Of RAS/BRAF wild type tumors at baseline, 4/5 (80%) showed additional point mutations. cfDNA quantitative measurements from this study closely mirrored changes in CEA and CT scan results, highlighting the importance of obtaining quantitative data beyond the mere presence of a mutation. Conclusions Our findings demonstrate the development of new RAS/BRAF mutations in patients regardless of whether they had pre-existing mutations in the pathway, demonstrating a convergent evolutionary pattern.

Developing realistic preclinical models using clinical samples that mirror complex tumor biology and behavior are vital to advancing cancer research. While cell-line cultures have been helpful in generating preclinical data, the genetic divergence between these and corresponding primary tumors has limited clinical translation. Conversely, patient derived xenografts (PDXs) in colorectal cancer (CRC) are highly representative of the genetic and phenotypic heterogeneity in the original tumor. Coupled with high-throughput analyses and bioinformatics, these PDXs represent robust preclinical tools for biomarkers, therapeutic target and drug discovery. Successful PDX engraftment is hypothesized to be related to a series of anecdotal variables namely, tissue source, cancer stage, tumor grade, acquisition strategy, time to implantation, exposure to prior systemic therapy, and genomic heterogeneity of tumors. Although these factors at large can influence practices and patterns related to xenotransplantation, their relative significance in determining the success of establishing PDXs is uncertain. Accordingly, we systematically examined the predictive ability of these factors in establishing PDXs using 90 CRC patient specimens that were subcutaneously implanted into immunodeficient mice. Fifty (56%) PDXs were successfully established. Multivariate analyses showed tissue acquisition strategy [surgery 72.0% (95% confidence interval (CI): 58.2–82.6) vs. biopsy 35% (95%CI: 22.1–50.6%)] to be the key determinant for successful PDX engraftment. These findings contrast with current empiricism in generating PDXs and can serve to simplify or liberalize PDX modelling protocols. Better understanding the relative impact of these factors on efficiency of PDX formation will allow for pervasive integration of these models in care of CRC patients.

Background Aberrant activation of the intracellular tyrosine kinase Src has been implicated as a mechanism of acquired chemotherapy resistance in metastatic colorectal cancer (mCRC). Here, the oral tyrosine kinase Src inhibitor, dasatinib, was investigated in combination with FOLFOX and cetuximab. Methods We performed a phase IB/II study of 77 patients with previously-treated mCRC. Primary objectives were to determine the MTD, dose-limiting-toxicities, pharmacodynamics, and efficacy. Using a 3+3 design, patients received FOLFOX6 with cetuximab and escalating doses of dasatinib(100, 150, 200mg daily), followed by a 12 patient expansion cohort at 150mg. Phase II studies evaluated FOLFOX plus dasatinib 100mg in KRAS c12/13mut patients, or in combination with cetuximab if KRAS c12/13WT. FAK and paxillin were utilized as surrogate blood biomarkers of Src inhibition, and paired biopsies of liver metastases were obtained in patients in the expansion cohort. Results In Phase IB, the dose-limiting-toxicities were grade 3/4 fatigue(20%), and neutropenia(23%). In Phase II, grade 3/4 fatigue(23%) and pleural effusions(11%) were present. Response rates were 20%(6/30) in the Phase IB escalation and expansion cohort, and 13%(3/24) and 0%(0/23) in the KRAS c12/13WT and mutant cohorts of Phase II, respectively. Median PFS was 4.6, 2.3, and 2.3 months, respectively. There was no evidence of Src inhibition based on surrogate blood biomarkers or paired tumor biopsies. Conclusions The combination of dasatinib plus FOLFOX with or without cetuximab showed only modest clinical activity in refractory CRC. This appears to be primarily due to a failure to fully inhibit Src at the achievable doses of dasatinib.