Treating breast cancer by novel WEE1 inhibitors

Project: Research project

Project Details

Description

Clinical development of new therapeutics for breast cancer to dampen the
tumor-induced immune suppression and help "wake up" the immune system to fight cancer is warranted.
Indeed, antibodies blocking the inhibitory signal triggered by the CTLA-4 and PD-1 on T-cells have emerged as
potent means to fight the immunosuppressive milieu (1-4). Despite the impressive objective responses in
cancer patients by targeting these immune checkpoint inhibitors, clinical benefits are yet modest. One potential
explanation is that tumor cells employ a number of different mechanisms to promote immune escape in the
context of breast cancer (5, 6), including the soluble factors (e.g. cytokines and metabolites) produced from the
tumor, and infiltration of different immunosuppressive cells in the tumor microenvironment such as myeloidderived
suppressor cells (MDSC) and T-regulatory cells (Treg) (7, 8). Novel therapeutic opportunity thus exists
in targeting these immunosuppressive pathways.
CD4+CD25+FoxP3+ Tregs, or other types of suppressive cells accumulating in the blood, and at tumor sites in
most patients and animals with cancer suppress antitumor immunity, seem to be a major mechanism of tumor
immune escape (8-11) and are particularly a crucial impediment to breast cancer immunotherapy (12). Several
cancer immunotherapeutics targeting Tregs, including Treg depletion, are currently being tested in the clinic.
Further, therapeutic benefit of immune-checkpoint blockade, such as anti-CTLA-4 therapy, could be attributed
at least in part to depletion of tumor-infiltrating Tregs (13-15). Thus, optimal strategies need for establishment
of reducing Tregs or impairing their suppressive activity in tumor, together with mobilizing and expanding
antitumor effector T cells.
WEE1 kinase phosphorylates and inactivates Cdk1/Cdc2-bound cyclin B, is a gatekeeper of the G2-checkpoint
arrest for premitotic DNA repair (16). WEE1 is overexpressed in various cancer types (17, 18). Notably,
preclinical studies (19-23) with breast cancer cell lines and animal models demonstrated that WEE1 inhibition
using siRNA or small molecule inhibitors reduced cancer cell viability, decreased tumor burden, and increased
survival, supporting the validity of WEE1 inhibition as a viable therapeutic target in breast cancer.
Combination of DNA-damaging cancer therapy (such as radiotherapy and/or cytostatics) with WEE1 inhibition
is a rational approach to push cancer cells in mitotic catastrophe resulting from premature entry into mitosis
with unrepaired lethal DNA damage (17, 18). Despite the direct cytotoxic activity, little is known about the effect
of WEE1 inhibition on host immune system. Interestingly, our preliminary data show that MK-1775 (AZD1775),
a selective and potent pyrazolo-pyrimidine derivative inhibitor of WEE1 (24), blocks the generation and
suppressive activity of Tregs while increasing the infiltration of antitumor CD8+ effector T cells in addition to its
direct cytotoxic effect on cancer cells. These results have led to a novel hypothesis that MK-1775
administration may augment breast cancer immunotherapy by suppressing Tregs. In this proposal, we will
characterize the phenotype and function of Tregs in the tumor microenvironment following MK-1775 treatment,
and explore the clinical potential of WEE1 inhibitors using the MK-1775 combined with PD-1 blockade in our
established breast tumor models. Our work will identify an unappreciated role of WEE1 inhibition in reversing
tumor-induced immune suppression and points to a novel and feasible bre
StatusFinished
Effective start/end date9/1/168/31/18

Funding

  • Northwestern Memorial Hospital (Agmt Signed 09/01/16)

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