PP2A: A Promising Biomarker and Therapeutic Target in Small Cell Lung Cancer
Abstract
Objective and Rationale: Lung cancer (LC) is the number one cause of cancer death in Veterans and military Service members in the United States. Surgery is the most effective therapy for solid tumors, and ~700,000 cancer patients have tumors removed each year. However, despite removal of the primary tumor, up to 20% of patients develop local recurrences and ultimately die. Local recurrences occur due to tumor cells that are not removed at the time of surgery and ultimately regrow. If human tumor tissue could be more readily visualized and better differentiated from normal tissue during surgery, cancerous lesions could be completely removed, reducing the probability of local tumor recurrence. Although several agents and strategies have been identified to prevent LC, an optimal strategy that does not cause drastic side effects has not been achieved. Therefore, there is an urgent need for more effective agents that can safely prevent LC development and spread without causing unwanted toxic effects. One approach to produce novel compounds is through the rational modification of well-established preventive agents. The resultant compounds may target cancers through mechanisms of action similar to those of the original agent, but with enhanced potency, reduced toxicity, and lower dose requirements. We have developed one such agent, LB100 (a PP2A inhibitor), which has shown promising effects in our preliminary studies. Our long-term goal is to develop this rationally designed, effective, and safe agent to treat and prevent SCLC. Areas of Emphasis: Our proposal is directly relevant to LCRP Area of Emphasis, To understand the molecular mechanisms of initiation and progression to lung cancer. Ultimate Applicability: What Types of Patients Will It Help and How Will It Help Them? Treatment with the novel small molecule LB100 will protect members of the general public from developing SCLC. LB100 will also help to control already existing tumors and reduce the recurrence of SCLC, thereby contributing to the treatment of all SCLC. What are the potential clinical applications, benefits, and risks? As per our preliminary studies, LB100 has been effective against SCLC in vitro and in vivo. The proposed studies will assess the bioavailability of LB100 in mice and assess its protective effects against SCLC in mouse models. In addition, this project will also assess and confirm the ability of miRNA and proteomic biomarkers, identified in our preliminary studies, to guide future clinical SCLC prevention trials. The overall results of the proposed studies will help us to determine how effective and generally applicable LB100 treatment may be to prevent the development of SCLC and to control aggressive, existing SCLC. Our preliminary studies also show that LB100 is effective and well tolerated in vivo without any overt toxicity. What Is the Projected Time Anticipated to Achieve a Clinically Relevant Outcome? We expect to complete the proposed studies within 3 years. Phase 1 and 2 trials could follow within a reasonable time frame, after approval from our Institutional Review Board (IRB) and an Investigational New Drug (IND) submission to the FDA. Public funding through foundation grants for preclinical and clinical studies is feasible if our results are promising. What Are the Likely Contributions of this Study to Advancing the Field of LC Research? The overall impact will be to reduce the incidence of SCLC and to improve the length and quality of life of patients with metastatic disease. The influence of this work will be enhanced by City of Hope’s status as a Comprehensive Cancer Center with unique facilities for clinical trials, enabling us to rapidly translate our findings for further on-site validation in preventive care. The efficacy and broad spectrum of the effects of LB100 in SCLC provides a strong rationale for its applicability to a wide range of SCLC tumor types. As described above, we believe t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310581
Entities
People
- Ravi Salgia
Organizations
- Beckman Research Institute of City of Hope
- United States Army