Not a scientist? Here is a summary of our work:
Developing New Drugs that Starve Cancer Cells to Death
Despite the introduction of exciting new “targeted” drugs and the success of immunooncology agents, patients are still dying of cancer. Why? Not all patients respond to these new therapies. In patients that do respond, the benefits are often temporary. In addition, metastatic disease that causes significant pain and limits quality of life continues to be very hard to prevent and treat. Clearly, bold new approaches must be tested if we are to significantly improve the lives of patients with late-stage cancers that are resistant to existing therapies.
Taking our inspiration from nature, we have designed a drug-like compound, SH-BC-893 (893), that has profound effects on tumor growth in animal models. 893 limits the growth of tumors in mice that spontaneously develop prostate cancer and kills several different classes of tumor cells taken directly from patients, both in a lab dish and when they are grown in mice. Importantly, 893 does not harm normal organ function. We performed bloodwork on mice treated with the anti-cancer dose of 893 for 3 months and found that liver, kidney, intestine, and bone marrow function was not compromised by 893. We have also performed studies evaluating whether 893 has the qualities of a good drug. The compound can be taken orally with once a day dosing, is not rapidly metabolized, and accumulates in tumors to much higher levels than it is present in the blood. These properties suggest that 893 could be a safe and effective new cancer therapy. We have started a company that is funding the safety studies that must be completed in multiple species before 893 can be given to patients and tested in clinical trials.
How does 893 work? We have shown in published studies that 893 kills cancer cells by starving them to death. 893 prevents sugars, proteins, and fats from entering cells and also disables the cell’s stomach preventing the digestion of more complex nutrients. Limited access to nutrients causes a hibernation response in normal cells; they survive by acting like bears in the winter. Cancer cells have mutations that prevent them from hibernating - when food becomes scarce, cancer cells die. While we understand that 893 starves cells, we do not understand exactly how it does it. Our current research seeks to identify the cellular proteins that bind to 893 and trigger cellular starvation. This information is essential to plan clinical trials with 893 in cancer patients.
Ghoulish Cancer Cells Fuel their Growth by Eating their Neighbors' Corpses
We are exploring an “outside of the box” strategy for cancer therapy that has never before been tested in patients: inhibiting macropinocytosis. Macropinocytosis refers to a process where cancer cells make large, tidal waves of cell membrane that scoop up material from their environment and bring it into the cell. The items they consume this way are digested in the lysosome (the cellular stomach) producing nutrients that cancer cells need to grow. Cancer cells use this scavenging technique to compensate for the fact that tumor blood vessels are abnormal and fail to deliver adequate amounts of fuel. We recently published a high-impact research paper showing that macropinocytosis promotes prostate tumor growth, and have now extended these studies to breast cancer. We hope to use inhibitors of macropinocytosis to controls tumor growth and progression. About half of late-stage prostate and breast tumors will be macropinocytic and would likely respond to drugs that block macropinocytosis. Because targeting macropinocytosis has never before been attempted, patients with tumors that have become resistant to all other treatments should still respond to macropinocytosis inhibitors. Because only a small number of normal cells are macropinocytic, we expect that this approach will not be very toxic.
One particularly gruesome discovery was that cancer cells feed on cellular corpses. More tumor cells live than die in a growing tumor - dead cells that were unable to tolerate the stressful tumor environment are always present. It seems counterintuitive, but the more dead cells present in a tumor, the worse the prognosis is for the patient. In fact, an accumulation of dead cells in a prostate tumor biopsy triggers the highest Gleason grade of 5. We may have an explanation for why dead tumor cells are such a threat: dead cells feed the surviving macropinocytic tumor cells. Every building block a cancer cell needs to proliferate can be harvested from dead cells, and macropinocytic cancer have no problem engulfing dead cell debris when it is present in their environment. This finding means that many cancer therapies might work better when combined with macropinocytosis inhibitors.