Spontaneous Regression of Cancer : Melanoma
Description
The spontaneous cancer regression process, a well-documented paradoxical natural phenomenon, shows that malignant tumors can episodically undergo complete permanent elimination without treatment, and thus may be used for incisive therapeutic design innovations. This approach has high novelty as spontaneous regression process displays no toxicity or recurrence, as compared to customary therapy, and thus duplicating such regression process is highly desirable. Our aim was to probe this phenomenon using computational biomolecular dynamics analysis, with application to malignant melanoma as illustrative case-study, and thereby identify candidate molecules that may mimic the spontaneous regression process on the tumor. We investigated microarray preparations of melanoma, finding two reciprocal phases: spontaneous progression and spontaneous regression, and showed 17 driver genes for spontaneous regression of melanoma. We probed gene ontology, differentially-expressed genes and network pharmacoinformatics analysis. Thereby we targeted two main melanoma signaling pathways (MAPK, PI3K-AKT) which we blocked in the bioinformatics platform by inhibiting two melanoma oncogenes (BRAF, NRAS), thus arresting the melanoma progression phase, and activating the reverse phase, melanoma regression. Through molecular docking, we investigated the interactions between oncogenes vis-à-vis candidate molecules, identifying alpelisib and cetuximab as promising repurposable pharmacological candidates capable of efficiently inhibiting both oncogenes. Molecular dynamics simulations elucidated the stability and structural dynamics of protein-ligand complexes over requisite time-scale. Notably, alpelisib demonstrated stable binding with both BRAF and NRAS, maintaining proper protein folding, and cetuximab exhibited continuous stable hydrogen-bonding with both targets, as we found from protein-ligand modelling. Furthermore, binding energy calculations highlighted electrostatic and van der Waals interactions in stabilizing protein-ligand complexes. Specifically, alpelisib exhibited strong van der Waals and electrostatic interactions with NRAS, indicating significant therapeutic potency. Our findings underscore the high impact possibility for leveraging the anomalous phenomenon of spontaneous cancer regression and developing targeted therapeutic interventions, with substantial clinical oncological potentials.