NOVEL THERAPEUTIC STRATEGIES FOR COLORECTAL CANCER

Rationale

Colorectal cancer (CRC) is a common and lethal disease. In almost 50% of all CRC patients, tumor cells from the primary tumor will spread to other parts of the body and develop metastases. The prognosis for patients with metastatic CRC (mCRC) remains poor. Clearly, novel therapeutic approaches are needed.

Results and Discussion

We therefore attempted to identify tumor characteristics in mCRC that are linked to poor-prognosis primary CRC tumors and that characterize established metastases. This might lead to the discovery of new leads for anti-cancer drug design.

ALDH1A1 - In order to form metastases, tumors must maintain a fraction of cancer stem cells (CSCs). Colorectal tumors consist of a small population of CSCs, which are generally less sensitive to treatment. CSC therapy resistance explains cancer recurrences even years after therapy has ended. This underscores the importance of targeting CSCs to yield durable clinical responses. CSCs are generally characterized by increased activity of ALDH enzymes. The ALDH superfamily has multiple biological functions that might affect tumor growth. One of the ALDH family members, the ALDH1A1 isozyme has been linked to colon CSCs. ALDH1A1 activity might thus be considered a property of colorectal CSCs. Of interest, ALDH1A1 has tumor-promoting and metastasis-promoting functions. An important question that needs to be answered is whether levels of ALDH1A1 are specifically related to features of poor-prognosis and metastases in CRC. Our results show that high levels of ALDH1A1 are associated with features of poor prognosis in CRC. For instance, ALDH1A1 levels were higher in liver metastases compared to primary CRC tumors. Moreover, ALDH1A1 was associated with right-sided colon carcinomas. Patients with right-sided colon carcinomas generally have a poor prognosis. Furthermore, our results suggest that ALDH1A1 levels are higher in patients with a poor prognosis.

Future Perspectives

The lack of therapeutics that can eradicate CSCs is hampering effective cancer treatment. Future studies assessing the potential of targeting the stem cell marker ALDH1A1 will be needed to answer whether ALDH1A1-targeting agents have clinical potency. Based on our data, we propose that primary tumor location should be taken into account when designing clinical studies with ALDH1(A1)-targeting drugs in CRC patients. Collectively, the data described in the thesis entitled ‘Novel therapeutic strategies for colorectal cancer’ provide novel leads for developing metastasis-targeting therapies and elaborates on strategies that will hopefully improve the prognosis of patients with CRC.