A pilot study to assess the status of PSMA as a theranostic target in advanced /heavily pretreated pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (pancreatic cancer) is a highly malignant tumour and is the 4th leading cause of cancer-related death. The survival rate for pancreatic cancer is generally low, with less than 20% of patients presenting with localized, potentially curable tumors. The overall prognosis for patients with unresectable tumors is dismal, with a median survival of 4.5 months for those with distant metastases. The overall 5-year survival rate among patients with pancreatic cancer is less than 5% .

The treatment of patients with advanced pancreatic cancer remains palliative, with a median overall survival ranging from 9 to 10 months . Chemotherapy is considered the standard of care in this setting, with gemcitabine being the treatment of choice. Multiple new agents in combination with gemcitabine have been tested in clinical trials, but none have shown a significant improvement in survival. The only agent that has shown a small improvement in survival is erlotinib, a small-molecule inhibitor of the epidermal growth factor receptor (EGFR). Overall, the prognosis for metastatic pancreatic cancer remains poor, with limited treatment options available.

Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein, a 750 amino acid metallopeptidase expressed predominantly in prostate cancer (PCa) cells . It has neuropeptidase and folate hydrolase activity, that is encoded by the FOLH1 gene located on the short arm of chromosome 11. Besides cell survival, it also plays a role in cell migration and nutrient uptake. The internalization process of the PSMA receptor allows for the bound molecules to reach significant concentration within the cell.

Apart from prostate cancer cells, PSMA expression is also found in the neovasculature of pancreatic cancers, triple-negative breast cancer, lung cancer, and certain other malignancies. Traditionally, patients with these cancers undergo a combination of surgery, chemotherapy, immunotherapy, and radiation therapy with palliative therapy in advanced metastatic cases.

177Lutetium (177Lu), with a half-life of 6.73 days when combined with PSMA ligands (such as PSMA 617) can be used for the destruction of tumor cells due to its medium‐energy β‐emission (497 keV) and a mean tissue penetration of 670 μm. It also emits low‐energy γ‐rays at 208 and 113 keV with 10 and 6% abundance respectively which allows for its imaging via gamma camera.

There is proven efficacy of 177Lutetium (177Lu) PSMA therapy in Prostate cancer(mCRPC) and in a few cases of glioblastoma multiforme (non prostatic malignancy) but to the best of our knowledge, no prospective study has evaluated the role of 177Lu-PSMA-617 in advanced/ heavily pretreated pancreatic ductal adenocaricnoma . Hence, the purpose of this study is to address this lacuna and to determine the role of PSMA as a theranostic target in the management of advanced pancreatic ductal adenocarcinoma.