Currently available treatments for advanced colorectal cancer (CRC) are primarily inefficient, and the prognosis remains poor, despite the introduction of targeted and immunotherapies. Although many combinations of therapies appear synergistic when tested in vitro, they fail in clinical trials. Thus, the response of individual cancer patients to therapy is generally unpredictable. Therefore, biomarkers for efficient drug combinations that can help prioritize patients' treatment are highly warranted. Prof. Straussman and his team identified specific biomarkers that predict the effectiveness of drug combinations for CRC. Their findings can be used as a tool for a personalized assessment of patients' responses to treatment options.
CRC is the third most common cancer in men and women1. CRC treatment options are limited for patients with advanced cancer, and current treatments are effective only in about 50% of stage 3 and less than 5% of stage 4 cancers. Moreover, even after the introduction of targeted and immunotherapies, treatment options for CRC patients have not changed dramatically, and the prognosis has not improved significantly either. Although many targeted therapies and combinations are promising in pre-clinical cell lines and mice, they fail to show effectiveness in clinical trials. Therefore, more effective treatments for advanced CRC are needed, as well as predictive biomarkers for efficient combinations or targeted therapies.
Prof. Straussman and his team identified specific biomarkers that predict the effectiveness of available treatments to CRC (specifically, a combination of MEK and SRC inhibitors).
Prof. Straussman and his team used Ex vivo organ culture (EVOC) of human CRC tissue to identify a subset of tissue that responds to drug combinations that showed promising synergistic results in previous in vitro screens. Most of the combinations that were found to be highly synergistic in-vitro were not effective when tested in EVOC. However, MEK/SRC combinatorial inhibition was effective in ~50% of the CRC human tissues examined. The team identified specific biomarkers that correlated with response to MEK/SRC inhibition, including high initial pSRC before treatment, the effectivity of SRC inhibition alone to reduce pERK in ex vivo slices, and the absence of G12 KRAS mutation. These findings can be used to identify patients likely to respond to treatment with combination MEK/SRC inhibitory drugs. Moreover, EVOC can also be further used for a personalized assessment of patient-specific CRC tumor's response to MEK-SRC inhibition.
- Biomarkers for effective CRC treatment using combination MEK/SRC inhibitory drugs
- Identify responding patient tumors as part of inclusion criteria for clinical trials to improve the chance of their success
- Tailoring personalized treatments for CRC
Prof. Straussman and his team and collaborators identified the mentioned biomarkers for effective MEK/SRC combination therapy using EVOC. A clinical study
Snapshot. Accessed December 13, 2021. https://www.cdc.gov/cancer/colorectal/statistics/index.htm
Gavert N, Zwang Y, Straussman R., et al. Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer. Nat Cancer. 2022 Feb;3(2):219-231. doi: 10.1038/s43018-021-00325-2. Epub 2022 Feb 10. PMID: 35145327.