Report
Teaser, summary, work performed and final results
Periodic Reporting for period 2 - THERACAN (Novel therapeutic strategies to treat pancreatic and lung cancer)
Teaser
A quarter of all solid tumors harbor a mutation in the KRAS oncogenes. Despite the identification of these mutations over 30 years ago, no selective drugs have been approved to treat these malignancies. Our aim is to identify and validate targets with potential therapeutic...
Summary
A quarter of all solid tumors harbor a mutation in the KRAS oncogenes. Despite the identification of these mutations over 30 years ago, no selective drugs have been approved to treat these malignancies. Our aim is to identify and validate targets with potential therapeutic value to devise novel strategies to treat these two human cancers with unacceptable low survival rates and unmet medical needs: pancreatic ductal adenocarcinoma and KRAS mutant lung adenocarcinoma. Although these tumor types have distinct pathological and clinical manifestations, they are both driven by KRAS mutations.
Our objectives are (1) to identify those genes activated in the cancer initiating cells responsible for the onset of pancreatic and lung tumors. We reasoned that genes implicated in the initial stages of tumor development will be maintained during tumor evolution and will not be affected by the intra-tumoral heterogeneity generated during tumor progression, (2) to identify and validate genes capable of reprogramming the stroma of pancreatic tumors to hamper its pro-tumoral effects, (3) to define the molecular events that control senescence, a naturally occurring process that serves as a barrier to tumor development, (4) to interrogate the role of known targets with suspected therapeutic value in tumor progression using a new generation of mouse tumor models that allow the temporal separation of tumor development from target ablation or inactivation. These studies will make it possible to design combination therapies capable of effectively eradicating advanced tumors, and (5) to validate these combination therapies using best-in-class inhibitors in state-of-the-art preclinical trial platforms based on mouse models and human tumor samples. The results derived from these studies will guide the design of new clinical trials that should have a positive impact in the treatment of these deadly diseases.
Work performed
No drugs have been approved to treat KRAS mutant tumors yet. It has been established that KRAS oncogenes drive tumor formation via activation of the MAPK pathway since genetic elimination of components of the MAPK pathway such as the MEK or ERK kinases completely prevented tumor formation. However, systemic ablation of these kinases in adult mice revealed unacceptably high levels of toxicity. Therefore, we have validated the role of c-RAF in lung and pancreatic tumors driven by mutant Kras based on the selective requirement for c-RAF in tumor initiation. We demonstrated that ablation of c-RAF expression in advanced lung tumors driven by KrasG12V/Trp53 mutations leads to significant tumor regression with no detectable appearance of resistance mechanisms. Tumor regression results from massive apoptosis. Importantly, systemic abrogation of c-RAF expression does not inhibit canonical MAPK signaling, hence, resulting in limited toxicities. Interestingly, in the case of the pancreatic cancer driven by Kras/Trp53 mutations in genetically engineered mice, although c-RAF inhibition alone did not show any effect, the combined ablation of EGFR and c-RAF expression resulted in complete regression of a significant percentage of tumors. Moreover, systemic elimination of these targets induces toxicities that are well tolerated. Response to this targeted therapy correlates with transcriptional profiles that resemble those observed in human tumors. These results open the door to the development of targeted therapies for patients.
Moreover, pancreatic cancer is characterized by the presence of abundant stroma primarily composed of cancer-associated fibroblasts (CAFs), that was suggested to stimulate tumor progression and to produce drug resistance as well as immunosuppression. Therefore, additional therapeutic strategies may include targets in stromal cells. We have compared the transcriptional profile of a subset of CAFs and normal pancreatic fibroblasts (PDGFRα+) isolated from our mouse model, and subsequently identified genes implicated in the protumorigenic properties of the CAFs, such as the Saa3/Mpp6 axis, that can have a potential therapeutic interest. Indeed, SAA1, the ortholog of murine Saa3, is overexpressed in human CAFs. Moreover, high levels of SAA1 in the stromal component correlate with worse survival. These findings support the concept that selective inhibition of SAA1 in CAFs may provide potential therapeutic benefit to patients.
Final results
Importantly, we have defined and validated in mouse models and in human samples new targets with potential therapeutic value. These targets were identified both in the tumor cells and in the stroma. Our results have allowed us to design new therapeutic strategies against lung and pancreatic cancer, two lethal diseases without current effective therapies in the clinic. Moreover, we continue working with the aim to identify and validate more targets with potential therapeutic value.
Unfortunately, for some of these identified and validated targets with therapeutic value there are no effective inhibitors. Therefore, we will further work in the development of better inhibitors and in designing alternative therapeutic strategies: inhibiting members of the same signaling pathway or by identifying new alternative targets/pathways.
Furthermore, we are currently working to pinpoint the resistance mechanisms that explain the lack of response to some of the strategies we have identified to unravel novel therapeutic approaches for these tumors. These studies will further lead to new therapeutic approaches.