Abstract P1-09-32: A novel candidate for chemotherapy induced alopecia (CIA) through local modulation of apoptosis and inflammation

Abstract

Abstract INTRODUCTION CIA, with an incidence of 65%, is considered by the sufferers as the most emotionally distressing side effect of cancer therapies. Cooling devices, the only option for CIA, have variable efficacy, and requires trained staff. To improve patient’s quality of life, the solution needs to address not only prevention, but also recovery (faster, non-patchy, in original quality) of hair, nails, eyebrows and eyelashes, in a self-medication setting. Normal hair cycle mainly consists of growth phase (anagen), regression phase (catagen) and resting phase (telogen) that precedes the shedding phase (exogen). The rapidly dividing anagen cells are damaged by chemotoxic agents and undergo apoptosis, inducing premature onset of the apoptosis-driven catagen phase. The intrinsic apoptosis pathway is essentially mitochondria dependent and executed by members of the Bcl-2 family. Androgenetic alopecia (AGA) subjects show remarkably low level of Bcl-2; Moreover p53 knock-out mice do not undergo CIA. These indicate that pharmacological inhibition of apoptosis pathways is key to effectively manage excessive hair loss, including CIA. In addition, apoptotic cells or cell debris will trigger and sustain scalp inflammatory condition by stimulating production of pro-inflammatory mediators, delaying hair regrowth process. Dampening inflammation is therefore essential to stimulate hair regrowth. APOPTOSIS MODULATION (STUDY N°1) OBJECTIVE: To demonstrate the molecular basis for proof of concept and safety through assessment of the candidate’s potential in modulating Bcl-2 towards normal level in AGA subjects. METHOD: After 3 months’ topical application, analyze, via immunohistochemistry, Bcl-2 level in scalp biopsies of male AGA subjects (n=20), and compare with Bcl-2 in non-AGA volunteers (n=25). RESULT: AGA subjects' Bcl-2 level is depressed (1.7). The candidate restored Bcl-2 (3.2) towards normal level (4.7). ATTENUATION OF INFLAMMATION (STUDY N°2) OBJECTIVE: To test, in vitro, the anti-inflammatory potential of the candidate. METHOD: To evaluate TNFα-induced expressions of the pro-inflammatory mediators (E-selectin, ICAM-1 and il-8) in endothelial cells (HUVECs) using specific Antibody Binding Capacity (sABC) technology, measured by flow cytometry. RESULT: The candidate is able to inhibit TNFα-induced expression of inflammatory marker/cytokine: E-selectin, ICAM-1 and il-8 in HUVECs. OPEN CLINICAL INVESTIGATION (STUDY N°3) OBJECTIVE & METHOD: To assess the candidate’s efficacy and tolerance, through topical application on female cancer patients, under supervision of oncologists/nurses (n = 11) RESULT: Candidate showed promising results in faster / non-patchy / original-quality recovery and prevention of CIA. Nail damages were generally prevented. CONCLUSION AND DISCUSSION In-vivo and in-vitro studies demonstrate that the candidate normalizes scalp apoptosis, a key to prevent CIA, and attenuates scalp inflammation, a key to promote faster/non-patchy/original-quality hair recovery. In cancer patients under chemotherapy, the candidate showed promising results in faster/non-patchy/original-quality recovery and prevention of CIA, although a higher dose may be required. Nail damages were prevented. Citation Format: JiaWei Liu, Saad Harti, Shiiba Tadafumi, Reiko Kondo, Angelo Mello, Geert Cauwenbergh. A novel candidate for chemotherapy induced alopecia (CIA) through local modulation of apoptosis and inflammation [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-09-32.