Ricerc@Sapienza

Acute T-cell lymphoblastic leukemia (T-ALL) is an aggressive blood tumor arising from early T-cell progenitors. Notch signalling is recognized as one of the key oncogenes responsible for the pathogenesis of T-ALL and its resistance to common chemotherapeutic agents. Several approaches to target Notch have been investigated and have proved their antiproliferative effects in T-ALL, however, their clinical implication is restricted by low efficacy and severe adverse effects, moreover, their combination with common antileukemic drugs does not look unequivocally beneficial. Since the prognosis of patients who experience relapse after the front-line therapy remains unfavourable, it becomes important to unveil the mechanisms underlying T-ALL chemoresistance and to discover new pharmacological agents or novel drug combinations with high potential for further clinical development. Previously, we identified a chalcone molecule, namely Compound 8 (C8), derived from naturally occurring chalcone butein, as an inhibitor of Notch signalling and cell growth in several Notch-dependent T-ALL cell lines supported by halted cell cycle progression and induction of apoptosis without affecting non-malignant Notch-expressing keratinocytes HaCaT. The proposed research aims to further investigate C8 as a drug candidate for T-ALL treatment by testing it in combination with pharmacological agents used for the treatment of T-ALL on several human T-ALL cell lines in order to identify the pros and cons of its alliances with different chemotherapeutic drugs in terms of synergy/additivity/antagonism and/or overcoming T-ALL resistance to antileukemic drugs. The evaluation of C8 effects in combination with conventional chemotherapy agents represents a necessary step for its development as an antileukemic candidate drug and would provide the basis for the design of novel and more efficient combinatorial treatment in T-ALL.