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Background: Despite our efforts to develop effective treatment paradigms, the overall success rates of most of the anti-cancer therapies for aggressive cancers remain very low. There is an urgent need to develop novel therapeutics to meet the present challenges. In recent years, several plant derived chemicals showed promising return as antineoplastic agents. Objective: Here, we evaluate the anticancer effects of one well known phytochemical Lupeol on a panel of aggressive cancer types in preclinical platforms. Methods: Melanoma (B16- F10), breast cancer (MDA MB- 231), Cisplatin resistant laryngeal cancer cell line HEp-2c, oral cancer cell line UPCI: SCC131 and prostate cancer (PC-3) cell lines were treated with different doses of Lupeol for 24 and 48 hours. Cytotoxic effects of these agents were measured by different endpoint assays. Matrigel tube formation, Limiting Dilution (LD) and sphere formation assay along with alteration in CD133 expression were performed. The expression status of Ephrin A2 and its downstream molecules were examined in aggressive mouse melanoma solid tumor in vivo. We also established the key findings in a patient derived ex vivo explant model (CANScript TM) for human breast and HNSCC tumors. Results: Viability (MTT) assay showed significant IC50 value for each cell lines treated with Lupeol followed by CFU assay. Concurrently, induction of apoptosis was found to be prominent in treatment arm. We also observed down regulation of CD133 expression and disrupted tube formation in all cell lines that together ascertain their ability to inhibit vasculogenic mimicry (VM). The ability of Lupeol to interfere with cancer stem cell (CSC) like properties was also evident where sphere formation and LD profile demonstrated alteration in the CSC pools for majority. The machinery of these effects suggested its link with Ephrin A2 and its downstream elements driving VM in melanoma in vivo tumour model. Further validation of these data in patient derived CANScript ex vivo setting where efficacy of this drug was tested on the patient tumors clinically progressed on standard of care (SOC). Discussion and conclusion: Together, these data suggest the promising roles of phytochemical in treating diverse cancer indications at aggressive or late stages of the diseases where existing paradigms frequently show limited efficacy. [ABSTRACT FROM AUTHOR]