Combined multimodal targeted therapy of pancreatic cancer to reduce side effects and enhance treatment specificity: drug testing platform and preclinical validation

Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer with poor prognosis and is projected to become the second leading cause of cancer-related deaths. Current treatments include surgery, chemotherapy, and in some cases irradiation. However, they fail to meaningfully extend the life of most patients and cause toxicities.

KRAS is frequently mutated in PDA.

Efforts to target KRAS have failed, partly due to the development of resistance mechanisms, such as activation of the ErbB pathway.

In this study, I will combine novel in vitro and in vivo models of PDA to identify drug combinations that are synergistic and less toxic.

I hypothesize that combined targeting of KRAS and the ErbB pathway will enable tumor cell targeting and will limit toxicities for non-malignant cells, thereby reducing side effects.

I will use co-cultures of non-malignant (derived from pancreatic, liver, colon, intestine, and kidney tissue) and tumor (derived from PDA patients or mouse models) organoids to study a multitude of treatment combinations. Aside from drugs targeting e.g.

KRAS and ErbB, I will test the additional effect of radiotherapy, the use of which is controversial for PDA treatment at present.

I will compare treatment responses of normal and malignant organoids and select the most viable results for in vivo validation.

This study is expected to identify novel treatment combinations for PDA and will elucidate the role of the tumor microenvironment in treatment responses of PDA cells.