Disease Team Therapy Planning I
Treatment of osteosarcoma by targeting osteosarcoam stem cells Osteosarcoma is the most common type of cancer that arises in the bone and occurs mainly in teenagers and young adults. There are approximately 900 patients diagnosed each year with this disease in the US. Approximately 80% of patients are diagnosed with localized disease while the remaining has either spread to the lungs (most common) and rarely to other bones. Osteosarcoma is treated with surgery and chemotherapy. With this treatment, about 65 out of every 100 patients diagnosed with localized disease are cured. Survival rates have not changed for this disease over the last 3 decades. Moreover, those who relapse or who are diagnosed with metastatic disease have a very poor prognosis where only 10-20 out of every 100 patients survive. Therefore, new treatments are urgently needed to improve treatment and survival for patients with osteosarcoma. One such treatment approach is to change the programming of cancer cells to make them behave more like normal cells-a process called differentiation. Retinoic acid and its derivatives (called retinoids) are agents that are used to cause differentiation of cancer cells in a variety of cancers. It is believed that “cancer stem cells” give rise to cancer. These cells are also thought to be responsible for resisting treatment and causing relapse that often leads to death. Only few of the cells in the tumor are “cancer stem cells”. Recent scientific data strongly suggest that cancer chemotherapy kills the majority of cells in a tumor but the “cancer stem cells” that are within the tumor escape and survive, leading to relapse. In the laboratory, we have identified a population of cells from osteosarcoma that have “stem cell” properties and call the osteosarcoma-initiating cells (OSIC). These cells can initiate osteosarcoma and cause tumors to grow rapidly when injected into mice that lack immune systems. OSIC have a receptor that can be targeted by retinoic acid that causes differentiation. A synthetic form of retinoic acid called Am80 that is much more powerful and binds more specifically to this receptor on OSIC is now available. By being more specific, it has fewer side effects when compared to retinoic acid. When used in the laboratory, it caused regression of osteosarcoma tumors that were created in immune deficient mice transplanted with OSIC-enriched cells. AM80 is approved for use in Acute Promyelocytic Leukemia (APL) in Japan and is already in clinical trials in the US for patients with APL and lung cancer. AM80 drug supply that is ready for use for treatment of patients is available. We propose to conduct a clinical trial in children, adolescents, and young adults with certain solid tumors that may respond to retinoids and specifically develop OSIC-targeted therapy with AM80 that will benefit patients with osteosarcoma.
Statement of Benefit to California:
Effective treatment of cancers with the least amount of toxicity will result better overall health and an improvement in productivity and is desirable. Standard treatment approaches for most cancers include surgery, radiation and chemotherapy. These result in significant suffering and decreased quality of life. Cancer stem cells are believed to be responsible for cancer initiation as well as resistance to treatment that results in relapse of the disease and death. Targeting cancer stem cells may lead to eliminating cancer and decreasing resistance to treatment resulting in more cures. Targeted therapy being more specific in action will result in fewer and less severe side effects leading to better quality of life and social contribution. Approximately 134,000 Californians were anticipated to be diagnosed with cancer in 2010 and 55,000 would die from some form of the disease (www.cdph.ca.gov). 1800 Californians are less than 20 years of age are diagnosed with cancer each year. Over the last two decades, the incidence of cancer has decreased by 15% for men and 9% for women in California. Simultaneously, the death rate decreased by 24% for men and 19% for women. It is estimated that there are 1.2 million individuals living in California today were diagnosed with cancer at some time point. California has the lowest lung cancer rates in the country and this can be attributed to successful tobacco control efforts. However cancer continues to be a leading cause of death and hospitalization resulting in significant health care costs as well as lost working days. AM80 is a drug that belongs to a family of drugs called retinoids and targets cancer stem cells in osteosarcoma, which is the most common bone cancer. It changes the cancer stem cells to make them more like normal cells thereby decreasing cancer formation and progression. Osteosarcoma occurs mainly in children, adolescents and young adults and has a cure rate of approximately 65%. This survival rate has not improved in the past 3 decades. Moreover, the survival of osteosarcoma patients who have advanced disease or who relapse is dismal with less than 20% of patients surviving two years. Treatment with AM80 may improve survival in osteosarcoma patients with fewer side effects. Since osteosarcoma occurs in young individuals, this will result in the maximum number of person-years saved by curing cancer. Additionally, AM80 will likely have broader applicability and show efficacy in other cancers such as lung cancer, ovarian cancer, certain skin cancers, bladder cancer, sarcomas, and several other childhood cancers. Since this clinical trial will be primarily conducted in California, our State’s economy stands to gain from the number of person-years that can be potentially saved as well as result in improved quality of life. Additionally, scientific insight gained from this innovative trial may further the biotech industry and lead to new discoveries.
EXECUTIVE SUMMARY Project synopsis The applicant seeks to develop a clinical trial examining the activity of the retinoid Am80 in osteosarcoma (OS), a bone tumor. Am80 is thought to induce the differentiation of putative cancer stem cells, the OS initiating cells (OSICs), thereby eliminating their tumor initiating potential. Am80 is already approved for clinical use in Japan for acute promyelocytic leukemia (APL), and is currently undergoing clinical testing in the US in APL as well as lung cancer. Am80 was designed to display improved target specificity when compared to a related compound, all-trans retinoic acid (ATRA), and may alleviate toxicities associated with the latter agent. The applicant aims to file an investigational new drug (IND) application, conduct a phase I trial and initiate a phase II study. Significance and Impact - While two-thirds of OS patients are cured by standard approaches including surgery, radiation and chemotherapy, some patients, especially those with advanced or relapsed disease, have a high mortality rate. Agents that improve clinical outcomes for those patients would be significant. - It is unclear whether Am80 has the potential for an improved toxicity profile over ATRA in the targeted OS patients. Patients with APL who are treated with ATRA rarely show the skin and other toxicities noted by the applicant, and toxicities associated with a condition known as retinoic acid syndrome would not be seen with either ATRA or Am80 in patients with solid tumors. - The proposal to study a single agent, Am80, to target cancer stem cells (OSICs) qualifies as an eligible therapeutic approach under this RFA. However, it is unclear whether OSICs are responsible for cancer relapse or progression in OS, since the preclinical data provided in the application were based on the analysis of a single OS cell line. - Responsiveness to the RFA is questionable since the selectivity of Am80 for putative OSICs has not been clearly demonstrated. Project Rationale and Feasibility - Reviewers felt that significant therapeutic responses to Am80 are unlikely based on previous clinical experience with retinoic acid-related compounds. Data to support the role of any retinoic acid-related agonists, such as ATRA, for the treatment of any relapsed refractory adult or pediatric sarcoma would have helped to alleviate this concern. - One reviewer thought that given the anti-OS activity of Am80 in the preclinical studies, a clinical trial using this agent is warranted. - The in vivo efficacy data for Am80 is not particularly convincing, since the studies rely on the use of a human OS cell line. Furthermore, the anti-tumor activity of Am80 appears to be only modestly increased compared to ATRA. - Since Am80 is already approved for the treatment of APL in Japan and is currently undergoing clinical testing in the US for several indications, a clinical trial utilizing this agent in OS is certainly achievable. - Extensive pharmacokinetic (PK) data is available for Am80 in several animal models and in humans from the APL study in Japan. It is thus unclear why additional PK studies, as proposed, are needed - The applicant did not justify the selected age range for the phase II study subjects, and the endpoints demonstrating efficacy, especially against OSICs, are not well defined. Principal Investigator (PI) and Planning Leader - The Principal Investigator has carried out the preclinical studies leading to the proposal, and is an experienced translational investigator, but has minimal experience in advancing molecules to the clinic or in carrying out clinical trials. - The Planning Leader is an experienced clinical pediatric hematologist and oncologist, who has been involved in numerous clinical trials and is well suited to carry out the planning proposal.