In spite of billions of dollars spent in the War on Cancer, cancer-specific mortality has changed little as a result, and the vast majority of cures are produced surgically, not from chemotherapy. The main problem is that even with early detection;most cancers still are detected too late and have metastasized before treatment. Although new therapies have less toxicity than older ones, the effect on cancer-specific mortality is small. The rationale for our proposal is that every metastatic tumor begins as a micrometastatic cell, and that these cells can be targeted to prevent development of advanced disease. Our hypothesis is that in apparently cancer-free patients, micrometastases are """"""""ticking time bombs"""""""" that eventually activate and kill the patient. We believe that research in our company's and our Founders'laboratories have identified a viable path to eradicating micrometastatic cells. Our assumption is that the reason micrometastatic cells do not begin growing immediately is that they are suppressed or made dormant by the normal extracellular matrix (ECM). We developed a novel, patented drug screen to identify compounds that target ECM-suppressed cancer cells in vitro that were used to screen 13,000 compounds to identify 3 lead compounds that also have very low systemic toxicity. These same compounds, DT310, DT320 and DT330, also target suppressed cancer cells in in vivo models, including orthotopic models involving natural metastasis. Because the compounds are fluorescent, their localization can be studied in cells. DT320 binds to a protein in the plasma membrane and also to the cytoplasm, whereas DT330 binds to a protein in the plasma membrane and to mitochondria. DT320 induces cell death by producing a G1S block and DT330 by a G2M block. The objective of this proposal is to identify the molecular target for these drugs. Identifying the target should allow for rational drug design and provide a mechanism of action for the current lead compounds. We plan to use affinity probes to identify the targets.
The first aim i s to modify the chemical backbone of two lead compounds in order to link them to magnetic beads or perform photoaffinity labeling without destroying the activity of the molecule.
The second aim i s to extract the target protein for identification by mass spectrometry and validate its identity by siRNA knockdown of the putative target to produce resistance to the DT agents. The identity of the target protein or proteins for these compounds is the deliverable for this proposal. Knowing the identity of the target protein will facilitate preclinical drug development for these agents tht target micrometastatic cells and, ultimately prevent metastasis. We envision these compounds would be given in a neoadjuvant mode.
This proposal seeks to identify the protein target for novel drugs that our company is developing that target micrometastases. These are cells that have broken off from the primary tumor, but which are not growing because they are suppressed or dormant from interactions with the normal extracellular matrix. Having this target will facilitate development of a new class of drugs that will prevent development of metastatic cancer by eliminating the cells that form them.
|Hurst, Robert E; Bastian, Anja; Bailey-Downs, Lora et al. (2016) Targeting dormant micrometastases: rationale, evidence to date and clinical implications. Ther Adv Med Oncol 8:126-37|
|Hurst, Robert E; Hauser, Paul J; You, Youngjae et al. (2015) Identification of novel drugs to target dormant micrometastases. BMC Cancer 15:404|