Not a scientist? Here is a summary of our work:
Developing Sphingolipids as Novel Drugs for Cancer and Obesity
Despite the introduction of exciting new “targeted” drugs and the success of new agents that activate the immune system to kill tumor cells, 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 tumor cells taken directly from patients. Importantly, 893 does not harm normal organ function. We have 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 by mouth with once a day dosing and is not rapidly metabolized. These properties suggest that 893 or a close derivative could be a safe and effective new cancer therapy. We have started a company, Siege Pharmaceuticals, that is completing the safety studies that are required before clinical trials in human patients.
We are also testing whether SH-BC-893 can be used to treat patients with obesity. Mice become obese when they are fed chow containing high levels of fat; this is done to simulate a “Western” (American) diet. When mice with obesity were given just 9 doses of 893 over 3 weeks, their body weight now matched that of mice eating a standard chow diet even though they continued to eat the high-fat food. Importantly, these mice didn’t just lose weight, their metabolic profile returned to normal. Insulin resistance, the precursor for diabetes, was reversed and toxic fat accumulation in the liver reversed. These robust improvements in whole body metabolism proved to be downstream of SH-BC-893-induced changes in the shape of mitochondria, the cells’ powerhouse. The most efficient mitochondrial shape is long and thin like spaghetti – making mitochondria small and round like meatballs is enough by itself to produce obesity, even if mice are eating healthy, low-fat mouse chow. It is believed that changes in mitochondrial shape also drive obesity in humans. We hope that 893 could be an effective therapy not just for obesity, but also for other metabolic diseases that result from changes in mitochondrial shape: heart disease, diabetes, fatty liver disease, neurodegenerative diseases like Alzheimer’s, and even chronic kidney disease.
We recently uncovered the cellular proteins responsible for the multifaceted effects of 893 on intracellular trafficking and mitochondria. It has multiple effects on cells, all of which work together to enhance metabolic health. 893 prevents sugars, proteins, and fats from entering cells by removing the transporter proteins for these nutrients from the cell surface. At the same time, SH-BC-893 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, living off their internal stores. Cancer cells have mutations that prevent them from hibernating – when food becomes scarce, cancer cells die because they don’t have adequate stores and cannot slow their growth. In addition, changing the shape of mitochondria changes the kind of fuel cells can burn, slowing cancer cell growth. Making mitochondria long and stringy like spaghetti also limits the generation of toxic reactive oxygen species (ROS) that damage cellular membranes and DNA; ROS are responsible for many of the changes associated with aging and cancer. Our ongoing research seeks to define the precise mechanism by which 893 and other, natural sphingolipids modulate cell biology. This knowledge will be critical for us to design safe and effective therapies that take advantage of the unique properties of sphingolipids. Sphingolipids are named after the Sphinx due to their enigmatic nature – we expect that it will take many years to completely unravel the complex ways these lipids alter cell biology.
Ghoulish Cancer Cells Eat their Neighbors’ Corpses to Resist Cancer Therapy
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 sort of like the way Cookie Monster eats cookies. The items they consume via macropinocytosis 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. Macropinocytosis is particularly important because it also plays a role in cancer drug resistance. Because many cancer chemotherapies target pathways that produce the building blocks for biosynthesis, scavenging nutrients via macropinocytosis is one way that cancer cells can become resistant to these drugs. Drug resistance is ultimately the reason why the cancer patients die. We hope to use inhibitors of macropinocytosis to control tumor growth and progression. We are currently investigating the signaling pathways that promote macropinocytosis to try to find a way to selectively disrupt this process in cancer cells but not normal cells so that we can uncover macropinocytosis inhibitors that will be safe and well tolerated.
One particularly gruesome discovery was that cancer cells feed on cellular corpses. Dead cells that were unable to tolerate the stressful tumor environment are always present in tumors. It seems counterintuitive, but studies have shown that 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.
Using sphingolipids to make genetic therapies work better
Sequencing the human genome has made it possible to design therapeutics that target the RNA products encoded by our DNA. While DNA contains the instructions that every cell uses to live, RNA is like the hands that build the protein tools necessary to execute the instructions found in DNA. Drugs that target RNA could change gene expression, providing a means to treat every human disease – therapeutics that can target RNA based on its genetic code have tremendous potential to improve human health. However, nucleotide-based drugs have a hard time crossing the cell’s membrane to reach the RNA targets inside the cell. Most of these nucleotide drugs and up in the lysosome (cellular stomach), a dead end compartment from which they can’t escape very well. We are using our knowledge of how cells move molecules between the plasma membrane and the lysosome to develop small molecules that increase the uptake of nucleotide therapeutics and their ability to escape from the membrane-bound vesicles that the cell forms around them. The drugs we have discovered so far can increase the activity of antisense oligonucleotides by as much as 300-fold by changing how they move through the cell. We are currently confirming that these compounds also make nucleotide therapeutics work better in various tissues of the body.