Lung cancer is the leading cause of cancer-related death in the United States and worldwide. Although there have been major breakthroughs that resulted from the increased understanding about how lung cancers initiate and progress to metastasis that is the more deadly situation, the development of targeted agents in lung cancer is still in its infancy. This is in part due to lack of promising targets that are known to be responsible for tumor initiation and metastasis in lung cancer, despite the Food and Drug Administration approval of some compounds that "turn off" an oncogenic protein called EGFR in lung tumors. Thus, it is critical for cancer researchers to find new promising therapeutic targets and develop strategies to block such targets in order to improve the clinical treatment and outcome of lung cancer patients.

There is a new field of cancer research that is under the spotlight, called cancer metabolism. Otto Warburg observed an interesting phenomenon about 90 years ago, which was named after him. The "Warburg effect" describes that how cancer cells handle their metabolism is quite different from normal cells. Cancer cells "eat" more glucose than normal cells, but use a very "wasteful" way, called glycolysis, to "break down" glucose to generate energy. Otto Warburg was awarded the Nobel Prize in Physiology or Medicine in 1931 for this finding. Recently, cancer researchers realized that glycolysis has its advantage to "fuel" cancer cells by providing not only energy in the form of a chemical called ATP, but also chemicals as "building blocks" for cancer cells to divide and tumors to grow rapidly. Therefore, such unique metabolic properties of cancer cells make cancer metabolism and glycolysis attractive targets in treatment of cancers; "turning off" glycolysis may only kill cancer cells or slow down their growth but leave normal cells alone.

However, how cancer cells coordinate the production of energy and "building blocks" for cancer cell growth and how crucial this is for tumor development and growth remain unknown. We found that a protein called phosphoglycerate mutase 1 (PGAM1) is important to coordinate glycolysis and generation of "building blocks" for cancer cells to grow by regulating a metabolic process called pentose phosphate pathway (PPP). This is a totally new finding in the cancer metabolism field. In addition, we found that "removal" or "turning off" of PGAM1 in lung cancer cells slowed down their growth and shrank tumors that grow in mice. These findings suggest that PGAM1 could be a promising target in treatment of lung cancer. Indeed, we found and developed chemical drugs that we named PGAM1 inhibitors (PGMI-004 and 004A). Such drugs effectively block lung cancer cell growth and tumor growth in mice, with no obvious side effects.

Thus, in this proposal, we will explore the molecular basis of how PGAM1 contributes to lung cancer metabolism and tumor growth. We will also continue to work with the current first generation of PGAM1 inhibitors and try using these inhibitors to kill a spectrum of human lung cancer cells and to reduce tumor growth from these cells in mice. Lastly, we will develop the next generation of PGAM1 with improved therapeutic effect, and the new drug design will be based on a "co-crystal" structure solved by us, which tells us where and how our drug binds to the target protein PGAM1 and turns it off. Such useful information will guide us to modify our current drug to generate more potent PGAM1 inhibitors.

Our studies will help to develop new therapeutic strategy to treat lung cancer patients. The PGAM1 small molecule inhibitors developed by us are promising anti-cancer reagents that could be applied in treatment of lung cancer patients. Our mouse-based work showed that these drugs do not have obvious effects in treatment of whole animals. In addition, treatment with PGAM1 inhibitors slow down the growth of leukemia cells isolated from human patients but did not affect the blood cells from normal healthy human donors. Therefore, our studies and compounds have shown that targeting PGAM1 is a promising anti-cancer strategy to treat human lung cancer patients, and completion of the proposed studies in 3 years is likely to provide the second-generation PGAM1 drugs that may be applied to initiate clinical trials to treat lung cancer patients.