Early Translational I
Cancer continues to take a heavy toll on human lives despite the billions of dollars that have been spent combating this disease, as well as the enormous amount of time and effort spent by scientists trying to find a cure. The basic strategies for treating cancer, which include surgery, radiation, and chemotherapy, are the same now as they were 25 years ago. There have indeed been improvements in each area; surgery is less disfiguring, radiation more precise and the drugs more potent. Yet, the casualties due to cancer continue to mount. Cancer is a disease in which a group of cells display uncontrolled growth and have the potential to spread to other parts of the body (metastasize). This group of cells is comprised of differentiated/drug sensitive cells, and a very small percentage of “cancer stem cells” (CSCs). These mutated cancer-causing cells or CSCs have been found and documented in primary leukemia, breast, lung, brain tumors, colon, prostate, pancreas etc. CSCs are also believed to be responsible for recurrence and metastasis. Current therapies are designed to kill the bulk of the differentiated/drug-sensitive cells but not the CSCs, which remain at least partially protected by multi-drug resistance genes leading to clinical recurrence and metastases. The Wnt signaling pathway has been shown to be critical in the regulation of stem and progenitor cells. Aberrant Wnt signaling has been associated with a wide range of malignancies. We have developed a small molecule drug-like inhibitor, ICG-001, that targets the Wnt signaling pathway. Using this inhibitor, we have discovered a cell’s fundamental decision-making point; when the protein β-catenin partners with the coactivator CBP, it leads to the turning-on of genes that are involved in proliferation or growth (a cell making an exact copy of itself). However, if β-catenin partners with p300, rather than CBP (p300 is a close relative of CBP), this partnership causes the cell to turn on a different set of genes that cause the cell to differentiate (lose its ability to proliferate and becoming a more specialized cell). The mechanism of action of ICG-001 is to prevent the partnering of β-catenin with CBP, thereby forcing β-catenin to utilize p300 as its partner. In so doing, the set of genes that are associated with recurrence and metastasis is now turned off. The uncontrolled growth of cells seen in cancer is also halted as ICG-001 forces the cancer stem cells to differentiate and become sensitive again to existing chemotherapies. Our research has shown that ICG-001 is effective in several mouse models of cancer (solid tumors and leukemias). ICG-001 also eliminates cancer stem cells. Importantly, it is non-toxic to normal cells and normal tissue stem cells at dose levels greater than 10 times the effective dose for at least 4 weeks of continuous administration. We are now proposing to make more potent and bioavailable CBP/β-catenin antagonists for human clinical trials.
Statement of Benefit to California:
Although luck plays a role, the big breakthroughs in medicine usually come from dramatic shifts in understanding and challenging the conventional wisdom. Antibiotics only came about after Pasteur and Koch provided the direct link between germs and disease (the germ theory of disease). Although highly controversial when first proposed, it is now a cornerstone of modern medicine & clinical microbiology. For cancer, a similar moment of enlightenment may have arrived. Despite the fact that all cancers are different in their complex details, the recent discovery of a common thread is wildly exciting. This common thread is the mutated cancer-initiating cells or “cancer stem cells” (CSCs). CSCs have been found & documented in leukemia, breast, lung, brain tumors, colon, prostate, pancreas etc. CSCs are believed to be the cause of recurrence and metastasis. Within a tumor, the bulk is comprised of drug sensitive/differentiated cells while CSCs represent only a small percentage of the malignancy. Current therapies are designed to kill the bulk of the drug-sensitive/differentiated cells but not the CSCs, which remain at least partially protected by multi-drug resistance genes, leading to recurrence and metastases. We have developed a small molecule drug-like inhibitor, ICG-001, that targets the Wnt signaling pathway – a pathway that is critical in the regulation of stem cells, and is associated with a wide range of malignancies. Using ICG-001, we have discovered a cell’s fundamental decision-making point: to turn-on genes that are involved in proliferation or growth (a cell making an exact copy of itself), or to turn-on a different set of genes that cause the cell to differentiate (lose its ability to proliferate and becoming a more specialized cell). The mechanism of action of ICG-001, in its simplest term, is to turn off the set of genes that are associated with proliferation in CSCs, in so doing forcing the CSCs to differentiate and become sensitive again to existing chemotherapies. Thus, ICG-001 eliminates cancer stem cells, recurrence and metastases. Our research has shown that ICG-001 is effective in several mouse models of cancer. Importantly, it is non-toxic to normal cells & normal tissue stem cells at dose levels greater than 10 times the effective dose for at least 4 weeks of continuous administration. We are now proposing to improve the drug-like qualities of ICG-001 with the goal of entering human clinical trials. The scourge of modern humanity is cancer. Despite the billions of dollars that have been spent combating this dreaded disease, scan the horizon and there is yet, no sign of a cure. Cancer remains the second leading cause of death in California. About 500 out of every 100,000 California State residents are affected by the disease. The cost in morbidity and mortality is staggering. This novel therapeutic to “cure” cancer by eliminating the cancer stem cells would have an immense positive impact to California and its citizens.
This proposal focuses on the development of small molecule drug candidates that target cancer stem cells (CSCs) from leukemia and advanced metastatic colorectal cancer. CSCs are thought to be associated with chemoresistance, tumor progression and metastasis. Most anti-cancer drugs eradicate the majority of drug-sensitive and “differentiated” tumor cells but may not affect CSCs. The applicant presents preliminary data from a lead compound that suggests anti-CSC activity. In Aim 1 the applicant proposes to generate a library of approximately 500 second-generation analogs of this compound and screen them for enhanced potency against the targeted molecular pathway. In Aim 2 the applicant will conduct preclinical testing of candidate compounds in mouse xenograft models using leukemia and metastatic colorectal cancer stem cells isolated from patients. In Aim 3 the applicant will perform preclinical IND-enabling studies in vitro and in mice, including detailed pharmacokinetic/pharmacodynamic (PK/PD) analysis and preliminary toxicology. Reviewers agreed that this proposal could have significant impact on the treatment of cancer. It is thought that CSCs are not susceptible to most cancer therapies, leading to clinical recurrence and metastasis. No effective therapeutic solution has been developed to treat CSCs to date. Reviewers felt that the rationale for pursuing the identified molecular target was excellent and supported by strong preliminary data with the applicant’s lead compound. They noted that the research plan was well designed with defined goals and measures of success. However, reviewers found the proposal lacking many important details. For example, information about the lead compound’s liabilities, stability, PK/PD profile, and already available analogs was lacking. Given that this lead compound was discovered 8 years ago, reviewers wondered why some of the work proposed hasn’t already been done. Additional serious issues were not addressed adequately, including the choice of targeted compound properties, methods of drug delivery, and justification for cell-based assays that are driving the structure-activity relationship analysis. The reviewers also advised that the order of proposed studies could be optimized. Reviewers praised the applicant and assembled research team as well qualified to carry out the proposed research. They noted that the researchers have the necessary expertise and successful track records in the field. Reviewers judged the research environment and resources to be excellent. They noted that the supply and consultant budgets seem high and are not well justified. Overall, reviewers felt that, although the impact, rationale and preliminary data for this proposal are strong, the research plan is missing important information that would have permitted a more complete assessment of its feasibility.