The role of NOTCH signaling in mediating rectal cancer resistance to chemoradiotherapy

• Applicants: Privatdozent Dr. Marian Grade; Professor Dr. Jürgen Wienands
• Subject Area: General and Visceral Surgery
• Term: since 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 288437061

Radiotherapy plays an integral part in treatment concepts for various tumor entities, including adenocarcinomas of the rectum. For locally advanced stages of this disease, the standard treatment involves preoperative chemoradiotherapy (CRT), followed by radical surgical resection. However, the response to CRT is very heterogenous, and ranges from complete response to complete resistance. This leads to a significant clinical dilemma, because patients with resistant tumors are afflicted with the potential acute and long-term side effects of both chemotherapy and radiation without a clear benefit. For these patients, (re-) sensitization of tumor cells would offer an attractive solution to a fundamental clinical and socioeconomic problem in oncology. On the other hand, patients with a complete tumor response after preoperative treatment may be spared from the morbidity and mortality of radical surgical resection. The concept to omit surgical resection in case of a complete clinical response after CRT, which is referred to as watch-and-wait strategy, is currently controversially discussed in the field. Because the individual patient’s responsiveness to CRT is so far unpredictable, more personalized treatment strategies are urgently needed. This, however, requires a mechanistic understanding of the cellular and molecular processes underlying CRT resistance, which is currently only fragmentary. During the past funding period, we demonstrated that the stimulation of inflammatory cytokine receptors of the gp130 family and the subsequent triggering of Signal Transducer and Activator of Transcription 3 (STAT3) conferred CRT resistance to rectal cancer cells. We used that knowledge to re-sensitize treatment-refractory cancer cells by blocking STAT3 function, and moreover, abolished the growth of STAT3-inhibited tumors in a xenograft mouse model. We also deciphered the mode-of-action of STAT3-mediated CRT unresponsiveness. STAT3 executed treatment resistance by triggering the expression of RBPJ, the key transcriptional regulator of the NOTCH pathway. Moreover, NOTCH receptor expression in pretherapeutic biopsies from patients treated with preoperative CRT correlated with clinical outcome. Altogether, our work of the past funding period uncovered an unprecedented alliance between gp130/STAT3 and NOTCH/RBPJ signaling that drives CRT resistance. In direct continuation of our work so far, we now aim at answering the following questions: (I) Which of the four NOTCH isoforms mediates CRT resistance by activating what kind of downstream effector pathway? (II) What is the role of the tumor microenvironment and does it contribute to NOTCH activation by providing the necessary ligands? III) Can NOTCH pathway inhibition be explored clinically to re-sensitize cancer cells to CRT?

• DFG Programme: Research Grants