Oncogenic signaling pathways in cancer mechanisms and drug discovery

The overarching theme of the immediate research in my newly established lab can be entitled “Oncogenic signaling pathways in cancer mechanisms and drug discovery”. Specifically, the oncogenic Wnt signaling pathway, a key driver in breast cancer and many other cancers, is within the focus of my research. Controlling multiple aspects of tumor pathology, from the initial oncogenic transformation to cancer cell proliferation and thus the primary tumor growth, to cancer cell migration and metastasis, dormancy, immune evasion, and radio- and chemo-therapy resistance, the oncogenic Wnt signaling pathway is a highly desired target for the anticancer drug development (1-3). Unfortunately, and rather uniquely among the signaling pathways, as of today the Wnt signaling remains untargetable. Although multiple inhibitors of the pathway have been discovered, none have advanced all the way to market approval, and the majority fail in preclinical or early clinical settings due to the intolerable side effects of the wide wiping out of this pathway due to the role of Wnt signaling in physiological processes in healthy tissues such as the intestine, the bone, and the hematopoietic system (4). My lab’s philosophy to efficiently yet safely target Wnt signaling in cancer is through development of inhibitors of the cancer-specific Wnt sub-pathways. Indeed, with 16 Wnt ligand proteins interacting with 10 FZD receptor proteins, and a multitude and diversity of the intracellular pathway components, certain cancer-specific targets within these sub-pathways can and should be identified and targeted with drug discovery and development (4). Two approaches to this task will be applied in the initial phase of the functioning of my laboratory at QBRI. The first is to develop nanobody-, aptamer-, and small molecule-based approaches to selectively antagonize individual FZD receptors, with the most immediate target being FZD7. This receptor has numerous confirmed functions in breast and other types of cancer, while in healthy tissues, its function is redundant with other co-expressed FZDs (5). We have previously demonstrated the effectiveness of this approach to selective small molecule antagonists of FZD5, another member of the FZD family, and the potency of these antagonists as selective and efficient inhibitors of colon cancer growth in vitro (tumor organoids) and in vivo (mouse models) (manuscript, patent application, and startup creation in preparation). We will now expand our high throughput-screening expertise to similarly target FZD7. Nanobodies, aptamers, and possibly small molecules will be utilized to develop multiple drug candidates selectively targeting FZD7. In the future, these candidates will be developed into clinical drug candidates against breast cancer, especially its most aggressive triple-negative subtype; a similar approach will also in the future be directed against other individual FZD receptors that may find applicability. The second approach stems from my earlier screening to identify drugs that can be repositioned against the Wnt pathway in triple-negative breast cancer (TNBC). This screening identified clofazimine, an anti-mycobacterial drug (used against leprosy and antibiotic-resistant tuberculosis), as a potent inhibitor of the cancer-specific Wnt signaling (6). Further studies showed its effectiveness against several other types of cancer (7), and its strong additivity with doxorubicin – one of the standard treatments in TNBC (8), bringing us to the repositioning clinical trials that were prepared in Geneva and that I hope to launch in Qatar in collaboration with HMC. Parallel molecular investigations revealed that clofazimine acts at a novel, previously unknown component of the Wnt pathway, possibly unique for the cancer cells (as clofazimine as safe in animal and human applications, unlike many Wnt inhibitors) (9). Target deconvolution we performed recently in collaboration with Karolinska Institute (Stockholm) resulted in identification of the list of ca. 20 potential targets of the drug in TNBC cells. Thus one of the tasks of my lab at QBRI will be to validate these targets. The immediate task – the target validation – will be performed through knocking down/out the individual candidates in cultured TNBC cells, monitoring the emanating effects on the TNBC cell proliferation, colony formation, migration, Wnt responsiveness, and clofazimine sensitivity. This line of research should lead us to the discovery of the novel, cancer-specific Wnt pathway component, which will further open novel translational research directions.

Hamad Bin Khalifa University (HBKU)