The biological origin, diagnostic value and therapeutic exploitation of the C-terminus chromogranin A naturally modified fragments in pancreatic cancer

Primary supervisor: Nikolitsa Nomikou, UCL

Secondary supervisor: Marilena Loizidou, UCL

Project

Pancreatic ductal adenocarcinoma (PDAC) is associated with very poor prognosis due to the late stage diagnosis of patients, when the disease is very difficult to treat with curative outcomes, while more than 70% of patients are diagnosed when the cancer is at inoperable stage. Survival of PDAC patients can be significantly increased with earlier diagnosis; however, diagnosing PDAC at early stages, remains challenging. The poor prognosis is also due to the recalcitrate nature of the disease, which is associated with its hypoxic profile and inadequately explored complex molecular processes that drive resistance-to-therapy and uncontrollable cancer progression.

The primary supervisor’s team has recently discovered a new mechanism of cancer resistance against reactive oxygen species (ROS) regulated by the naturally-modified fragments from the enzymatic degradation of the C-terminal region of chromogranin A (CgA). The latter phenomenon is particularly prevalent in PDAC, and it has been found that CgA degradation fragments are detectable in blood samples of patients with PDAC, even at the early stages of the disease.[1] However, the modified C-terminus fragments, thus far, not been explored or exploited in PDAC detection/diagnosis/prognosis, while its effects in cancer progression and response-to-treatment have not been investigated. The aim of this project is firstly to investigate the biological origin of these moieties, with regards to the factors that promote their formation and subsequent chemical modification, either intracellularly or in the PDAC tumour microenvironment (TME). Using human PDAC cell lines, the level of chromogranin A fragmentation, C-terminus fragment formation, modification, and secretion will be investigated under normoxia and hypoxia. This will allow the interrogation of their biological origin, as well as the conditions that encourage their formation.

The second part of the project will involve exploring the potential of these moieties as diagnostic blood biomarkers for early stage PDAC. In this project, a nanotechnology-assisted method, exclusively designed by our research group, for the detection and quantification of peptides bearing the specific chemical modification, will be employed. Plasma samples spiked with the modified peptides, and potentially, plasma samples of PDAC patients (Ethics Approval already obtained) will be processed for analysis to explore the potential of these moieties in early PDAC detection.

It has been suggested that the CgA fragmentation pattern defines the behaviour of malignant cells and can be important for evaluating the level and mechanism of cancer resistance.[2,3] In our own studies we have seen that the moieties suggested for investigation in this research proposal are associated with resistance to ROS-mediated treatments.[4] In fact, we have managed to reverse this resistance-to-treatment by inhibiting the effects of these moieties, both in vitro and in vivo, in experimental prostate cancer models (unpublished material – IP protection pending). Hence, the third part of the project will involve investigating the potential of augmenting the therapeutic outcomes of ROS-mediated therapies, such as platinum-based chemotherapy, against PDAC, by abolishing the cell-protective effects of these moieties.

References

1.  Reni M, Andreasi V, Gasparri AM, Dugnani E, Colombo B, Macchini M, Bianco M, Dallatomasina A, Citro A, Assi E, Protti MP, Esposito A, Falconi M, Curnis F, Piemonti L, Corti A. Circulating chromogranin A is cleaved into vasoregulatory fragments in patients with pancreatic ductal adenocarcinoma. Front Oncol. 2020;10:613582.
2. Curnis F, Colombo B, Corti A (2023). Quantification of chromogranin A and its fragments in biological fluids. In: Borges, R. (eds) Chromaffin Cells. Methods in Molecular Biology, vol 2565. Humana, New York, NY.
3. Mahata SK, Corti A. Chromogranin A and its fragments in cardiovascular, immunometabolic, and cancer regulation. Ann. N.Y. Acad. Sci. 2019;1455:34-58.
4. Pasqua T, Tota B, Penna C, Corti A, Cerra MC, Loh Y P, Angelone T. pGlu-serpinin protects the normotensive and hypertensive heart from ischemic injury. J Endocrinol. 2015;227(3):167-178.