Kurt Richard Weiss, MD
Assistant Professor, Department of Orthopaedic Surgery, Division of Musculoskeletal Oncology, Director of the Cancer Stem Cell Laboratory, University of Pittsburgh Medical Center
2013 Sarcoma Foundation of America Research Grant Recipient: “Investigation Of Novel Anti-Metastatic Therapy For Osteosarcoma”
PLEASE DESCRIBE THE FOCUS OF THE RESEARCH PERFORMED IN YOUR LAB.
Although there are dozens of distinct histologic subtypes of sarcoma, they all share one deadly characteristic: the propensity to metastasize (spread) to the lungs. Indeed, pulmonary metastases are the main cause of mortality in sarcoma patients of all ages. Although the diagnostic, surgical, and supportive care of sarcoma patients has steadily improved, the overall survival for these diseases has not. For example, a child diagnosed with osteosarcoma (the most common bone sarcoma) today has roughly the same prognosis as a child diagnosed 25 years ago. This failure to improve sarcoma prognosis has been borne out by research from many centers all over the world, and is clearly unacceptable. We must do better!
The mission of the University of Pittsburgh Cancer Stem Cell Laboratory is to understand the molecular and cellular processes that allow sarcoma cells to leave the primary tumor and spread elsewhere in the body. Once understood, these processes can potentially be interrupted. If sarcoma cells are denied their ability to spread throughout the body, the incidence of metastatic disease will decrease and survival will improve.
In the Cancer Stem Cell Laboratory, we use a variety of in vitro and in vivo techniques to study sarcoma metastases. Molecular techniques allow the study of genes and proteins that affect sarcoma cells. Cell culture enables us to study how individual and groups of sarcoma cells behave under different conditions. Animal models facilitate our ability to test promising treatments in the complex setting of a living creature, and hopefully pave the way for novel treatments. Clinical outcomes studies allow us to constantly evaluate and improve the care delivered to our patients.
All of these contribute to the pursuit of our ultimate goal: to eliminate sarcoma metastases and save the lives of our patients.
WHAT HAS INSPIRED YOU TO RESEARCH SARCOMA?
In 1989 I was diagnosed with osteosarcoma in my right tibia bone. Unfortunately the sarcoma had already spread to my lungs at the time of diagnosis. Despite surgery to remove the tumors from my leg and lungs, and aggressive chemotherapy, the sarcoma still came back into my lungs. This was a very grave situation.
At this time I enrolled in an experimental clinical trial of muramyl tripeptide phophatidyl ethanolamine (MTP-PE) that was offered by Dr. Eugenie Kleinerman at the MD Anderson Cancer Center in Texas. Miraculously, the experimental treatment saved my life and taught me emphatically that sarcoma medical research and clinical trials save lives. I decided to become a sarcoma physican/scientist and devote my life to the study of sarcoma biology, and the care of sarcoma patients.
PLEASE SHARE A BIT ABOUT THE PROJECT THAT WAS FUNDED BY YOUR SFA RESEARCH GRANT AWARD.
As mentioned above, conventional chemotherapy has not improved the survival of patients with osteosarcoma and other sarcomas for decades. Survival is mainly determined by the presence or absence of metastatic spread to the lungs. Clearly, we must do a better job of understanding the biological processes that allow sarcoma cells to spread.
We learned from several years of in vitro molecular biology and cell culture experiments that osteosarcoma cells rely on stem cell factors such as aldehyde dehydrogenase (ALDH), mammalian target of rapamycin (mTOR), and Notch1. All of these seem to help osteosarcoma cells move, invade, and resist stress. With our animal model of metastatic osteosarcoma, we wanted to test the ability of ALDH inhibition, mTOR inhibition, Notch1 inhibition, and combination therapy to decrease the ability of osteosarcoma cells to spread to the lungs.
The first and most important step was to make several improvements to the animal model, and thus make it as similar as possible to the osteosarcoma experienced by real patients. We have made many important changes to the animal model and these are ongoing. We have also begun treating experimental animals with stem cell factor inhibitors to see if they can decrease osteosarcoma metastases.
It is likely that all sarcomas use the same basic biological processes and programs to metastasize throughout the body. Our hope and expectation is that the discoveries we make with osteosarcoma will be useful for the treatment of other sarcoma types as well.
HOW HAS FUNDING FROM THE SARCOMA FOUNDATION OF AMERICA HELPED IN YOUR RESEARCH EFFORTS?
The support of the SFA has been vital to the development of our animal model of osteosarcoma and our ongoing efforts to understand and treat sarcoma metastases. Personally, it has been very rewarding to be recognized by our largest national sarcoma research and patient advocacy foundation. We at the University of Pittsburgh Cancer Stem Cell Lab are grateful for the past, present, and future support of the SFA. We will never stop looking for new ways to stop sarcoma metastases!