Research on Late-stage Cancer
It is widely understood that late-stage cancers are more aggressive than early-stage cancers and are more often responsible for patient mortality.
It is also well known that tumors that have metastasized to distant sites are more likely to die from cancer than patients who have no large (macro-) metastases.
Recent advances in our understanding of late-stage cancers have demonstrated that:
1. Cancer cells escape from the primary tumor site to distant sites relatively early in the tumor process.
2. Cancer cells evolve by both genetic and epigenetic mechanisms in both the primary tumor site and in the metastatic colonies.
3. Metastatic colonies can exist in a latent or dormant phase in secondary organs. These may exist as single cells or as small micro-metastases. Importantly, these small tumors do little harm to the patient and many patients live a normal life while carrying many small metastatic colonies.
However, when the small micro-metastases are induced to grow, the new larger (macro) metastases can cause significant harm to and ultimately patient death.
Questions being pursued in our laboratory:
Why do patients die of cancer? The current dogma is that macro-metastases grow up and take over essential organs (such as lung, brain, liver, and bone marrow), causing these organs to fail and consequently leading to patient death. We believe that other mechanisms contribute to cancer mortality. These are mediated by molecules that are released by the metastases and circulate to other organs, causing loss of function in distant organs. Consequences of this are liver failure, clotting abnormalities, loss of brain function, inflammation, and immune function loss.
Can we find drugs that work better on late-stage cancers? If tumors evolve, as they progress from early to late-stage, perhaps they will respond differently to drugs in each stage. We performed a drug screen designed to find drugs that preferentially killed late-stage tumors. We found a few strong candidates, many of which were also in use as anti-parasite drugs (anti-helmintics). Working with Dr. Lijun Sun at the Beth Israel Deaconness Hospital, we have designed new forms of these drugs that can more easily reach metastatic tumors. We are currently analyzing the mechanism of action and best means of delivery of these new drugs in order to move them rapidly toward clinical development.
To read more, see: Cheong JE, et al., Synthesis and anticancer activity of novel water soluble benzimidazole carbamates. European Journal of Medicinal Chemistry 2018; 144:372-385.
Front photo: Routes of cancer spread in prostate cancer. Image adapted by G. Gundem, Nature, 520(7547), 353-357, 2015