From the regulatory role of PDPN in mTOR/PI3K/Akt signaling to clinical trials

The mTOR/PI3K/Akt pathway is the most frequently altered network in human neoplasms. Mutations leading to the activation of this pathway or the closely related AGC kinases is associated with cancer initiation, progression, metastasis and drug resistance.
Collective invasion is one way for cancer cells to disseminate effectively to distant organs and is essential for tumor progression. Podoplanin (PDPN) is a marker for collective invasion at the invasive front in several malignancies. PDPN is known to interact with some ECM proteins and have multiple roles in the immune compartment but how PDPN is regulated is poorly understood.
Here, we aimed to decipher the mechanisms of regulation of PDPN from patients biopsies and in vitro. Secondly, we aimed to evaluate the efficacy of a combined treatment with an clinical mTOR inhibitor and a targeted radionuclide in a pancreatic neuroendocrine tumor mouse model. Lastly, we intended to investigate a novel combined PI3K-mTOR inhibitor pharmacodynamic properties using serial needle biopsies from advanced cancer patients.
The EGFR-dependent activation of Akt and STAT3 is regulated by PDPN. Our results support a role for PDPN as a potential biomarker of resistance to EGFR tyrosine kinase inhibitors already approved in the clinic in malignancies such as non-small cell lung cancer.
Then, we demonstrated efficacy of both treatments alone and the potential of combined treatment. Everolimus is only effective when given daily. Finally, The maximum tolerated dose of PQR309 is 80 mg of orally. Pharmacokinetic is dose-proportional and pharmacodynamic shows PI3K pathway phosphoprotein downregulation in paired tumour biopsies. Clinical activity was observed in patients with and without PI3K pathway dysregulation.
Together, these three diverse projects provide novel insights on the impact of PDPN and other treatments on the mTOR/PI3K/Akt pathway.