FOR2036

Overview

Bcl-2 family proteins are core regulators of the intrinsic pathway of apoptosis, acting on
mitochondria through complex interactions within the family. Thus, an intricate insight into
their regulation is highly important for understanding physiology and disease and for creating
novel treatment paradigms. Indeed, small molecules inactivating anti-apoptotic Bcl-2 proteins
effectively kill cancer cells and have entered phase-II/III clinical trials. In fact, April 11th 2016
marks the first FDA approval for one of these compounds.

While the field of apoptosis and Bcl-2 family research has arrived at the bedside, there is a
distinct lack of knowledge on a number of critical issues. Our consortium helps to gain
relevant ground on some of these issues and aims to address questions, unanswered in the
field, in a highly collaborative approach in 3 work packages (WP).

WP1: Despite a basic understanding of apoptosis, the real ordering of events for cell death
execution within the Bcl-2 family is still relevantly unclear. WP1 will address the role of
stochiometry, complex formation, membrane interaction and post-translational control of Bcl-
2 family interactions with advanced methodology, ranging from advanced microscopy
investigations into biophysical properties to sophisticated protein chemistry.

WP2: The limited knowledge on the interaction between Bcl-2 regulated apoptosis and other
cell death or proliferative pathways connects to relevant clinical questions. WP2 will elucidate
interactions of the Bcl-2 family with cell cycle and the death receptor pathway, and will
explore currently uncharted cellular stress responses in biologically relevant models.
Approaches include cell biology assays on primary tissues, mitotic cell death analysis and
modelling approaches integrating data spanning biophysics to cell biology.

WP3: The exciting FDA-approval of a first-in-class Bcl-2 inhibitor pairs with a critical shortage of essential knowledge for further development of these drugs. In fact, early insights into
toxicities, the lack of clear knowledge on resistance mechanisms and relevant biomarkers
impede treatment success. In WP3 clinician scientists tackle such questions by establishing
Bcl-2 family expression profiles from unique clinical sample sets and bridging functional
questions into disease models. Maps of clinical materials will connect to interventional mouse
models allowing important insights into CLL, AML/MDS and unique paediatric tumors.

Next to the proven track-record of collaboration of the group the proposal contains extensive
crosstalk within and between work packages ensuring a continued high output in terms of
discovery and translational potential. We expect to gain relevant ground on a number of
unanswered questions, critical for understanding the basic biology of cell death and clinical
development in a number of diseases.