Scientific abstract
Epithelial ovarian cancer (EOC) and pancreatic ductal adenocarcinoma (PDAC) are two of the most
devastating human malignancies in desperate need for improved treatment concepts. Treatment resistance in
cancer therapy frequently includes, among others, reduced drug uptake, increased drug efflux, improved
adaptation to chemotherapy-induced stress/DNA damage and inhibition of apoptosis. An example of such a
resistance mechanism is the X-linked inhibitor of apoptosis proteins (XIAP), a potent negative regulator of
caspases and promoter of cancer cell survival in both ovarian and pancreatic cancer. Inhibition of XIAP has
been studied to increase apoptosis and to overcome drug resistance in vitro and in preclinical mouse models.
Second mitochondria-derived activator of caspases (SMAC) is an endogenous inhibitor of both XIAP and
cellular IAP (cIAP) by reactivating caspase activity (XIAP blockade) and cIAP degradation, leading to cancer
cell death. These findings have initiated the development of synthetic small molecule mimics of endogenous
SMAC, which have been studied in a wide variety of human malignancies either as single agents but also in
combination with systemic chemotherapy as a means to further improve patient outcomes.
The foundation of our work with respect to small molecule drug development is based on sigma-2 ligands (S2)
that facilitate fast and selective uptake into the cancer cells due to ~10-fold higher abundancy of the
corresponding sigma-2 receptor (S2R) compared to normal host cells. By generating chemical conjugates
between S2 and a variety of small molecule drug cargos, we are now capable of delivering therapeutic
payloads more efficiently and selectively than their non-targeted counterparts to the tumors (targeted therapy).
LCL161 is a clinically explored IAP inhibitor (IAPinh) that induces target activation but failed to demonstrate
objective responses in patients. In this grant, we propose to study an innovative experimental cancer
therapeutic by chemically linking IAPinh (LCL161) to S2 ligand SW43, resulting in S2/IAPinh for tumor-
selective drug delivery and therapy. We hypothesize that S2/IAPinh can be combined with systemic, low-dose
chemotherapy to result in synergistic treatment regimens that lead to tumor eradication while systemic
toxicities are reduced to a minimum.
The overall goal of our current study is to find effective therapies for ovarian and pancreatic cancer. The
proposed aims maximize the chance that a novel drug candidate, S2/IAPinh, will be effective clinically. This is
envisioned either as single-agent, low-dose S2/IAPinh therapy in the context of a TNF-α gene signature in
patient tumors or as combination regimens with clinically approved pathway enhancers, such as Nab-paclitaxel
(Abraxane) (ovarian cancer) and Gemcitabine/Nab-paclitaxel (pancreatic cancer) but also statin-based
inhibitors of cholesterol de novo synthesis. Our new findings represent an exciting innovative opportunity to
enhance the activity profile of S2/IAPinh employing novel drug combinations for the benefit of cancer patients.