Early Translational II
$1 724 361
In the United States and in California, lung cancer is the leading cause of cancer death, killing more patients than breast, colon, and prostate cancers combined. Although tobacco smoke is the predominant risk factor for development of lung cancer, clinical observations suggest that the percentage of never smokers among lung cancer patients is steadily increasing, especially among women. Non-small cell lung cancer (NSCLC) is the predominant type of lung malignancy, representing about 85% of all cases. Although use of chemotherapy has helped to reduce NSCLC mortality, the five-year survival rate of patients with advanced disease remains at 15%, a rate that has been unchanged for over 20 years. It is clear that new therapies are urgently needed. The poor prognosis of NSCLC is often due to development of resistance to chemotherapy. Recent reports indicate that lung tumors contain subpopulations of cells, termed cancer stem cells, that account for less than 5% of the bulk tumor mass, but are largely responsible for drug resistance and consequent tumor recurrence. Importantly, the chemoresistance of cancer stem cells is reversed by parthenolide, a naturally-occurring compound reported to have strong antitumor activity in leukemia and prostate cancer. Anticancer effects of parthenolide appear due to its inhibition of tumor survival proteins that are markedly increased by administration of chemotherapy, with blockade of these survival proteins leading to reversal of chemoresistance. Although parthenolide selectively kills cancer stem cells, it has poor pharmacologic properties for use in the clinic. We hypothesize that use of parthenolide to selectively kill drug-resistant cancer stem cells in lung cancers may be a new strategy to eradicate NSCLC. To test this idea, new parthenolide analogues with improved bioavailability and antitumor action will be designed and synthesized in the chemistry laboratory. Then, drug-resistant cancer stem cells will be selected from bulk NSCLC cells, and reversal of chemoresistance by parthenolide analogues will be evaluated in the oncology laboratory. Promising anticancer compounds will then be assessed in human lung tumor xenograft models in vivo, with parallel studies to determine bioavailability and potential clinical utility. Further development of new targeted agents to kill drug-resistant cancer stem cells may significantly improve patient survival in the clinic. Thus, the proposed research will lead toward a development candidate based on cancer stem cells that will address an unmet medical need, namely the treatment and eradication of drug-resistant cancer stem cells in patients afflicted with lung cancer.
Statement of Benefit to California:
The proposed research can have important benefits for the state of California and its citizens. According to recent reports on cancer incidence and mortality, about 17,910 individuals in California will be diagnosed with lung cancer this year and an estimated 12,750 Californians die from lung cancer annually. Although most lung cancers are a result of tobacco smoking, approximately 25% of lung cancer cases worldwide are estimated to be not attributable to tobacco use, accounting for over 300,000 deaths worldwide each year. In newly diagnosed non-small cell lung cancer, the predominant type of lung cancer, clinical observations suggest that 10% of men and 20% of women, with a much higher proportion among Asiatic women, have never smoked (never smokers). In general, current therapies for lung cancer have had only limited success, with a 5-year survival of about 15% for patients with advanced disease. Development of a new therapeutic targeting lung cancer stem cells that drive tumor progression can lead to more effective suppression of lung cancer and markedly advance patient survival in the clinic. Further, an orally-available anticancer agent may significantly reduce the high costs of medical care due to administration of intravenous chemotherapies and management of associated side-effects of these cytotoxic treatments.
The goal of this Development Candidate Feasibility (DCF) proposal is a new strategy to eradicate cancer stem cells (CSCs) in the treatment of non-small cell lung cancer. The approach is focused on the development of new parthenolide (PTL) analogs with improved oral bioavailability, reduced toxicity for normal cells, and increased anti-CSC activity. The application is based on the hypothesis that CSCs, although they comprise only a small portion of a tumor’s bulk mass, are responsible for drug resistance and tumor regeneration after standard cancer therapy. Aim 1 proposes to isolate drug-resistant non-small cell lung CSCs from bulk human tumor cells. Aim 2 assesses the properties of chemotherapy-resistant non-small cell lung CSCs for CSC biomarkers, behaviors, and pathways that block chemotherapy-induced cell death. Aim 3 attempts to synthesize and test the antitumor efficacy of PTL analogs alone and combined with standard chemotherapy in vitro and in vivo using human lung tumor xenograft models. Reviewers recognized that the project could have a potential impact by addressing an unmet therapeutic need in the treatment of non-small cell lung cancer. However, they voiced serious reservations about the proposal’s rationale. This proposal is based on preliminary data suggesting that cisplatin, a standard chemotherapeutic agent, does not target particular CSC lines but that PTL targets such CSCs that have been exposed to cisplatin in vitro. While these results imply that PTL targets lung CSCs, reviewers did not find this evidence compelling and suggested that the application would have been strengthened by rigorously characterizing the derived CSCs and providing direct evidence that PTL could target CSCs in vivo. Additionally, the reviewers challenged the proposal’s basic assumption that current cancer chemotherapeutic agents do not target CSCs in lung cancer and were unconvinced by the central assertion that chemoresistance defines and identifies CSCs. Reviewers expressed serious concerns about the application’s feasibility and research plan. Reviewers cited the omission of significant details, lack of rationale for many of the proposed assays, and an absence of the most rigorous test to functionally assess CSCs. Rationale for the selection and evaluation of the chosen cell lines was lacking. Plans were inadequately presented (or absent) for assessing and prioritizing PTL analogs, monitoring toxicity and exposure, and identifying and characterizing pathways targeted by PTL. The reviewers acknowledged the Principal Investigator’s (PI) considerable work and expertise in breast cancer and more limited experience in lung cancer. The research team is well qualified in terms of chemistry, cell biology, and animal testing, and they have excellent access to facilities and support from the host institution. However, reviewers noted that the PI lacks experience in the CSC field and has limited experience in drug development. In summary, this DCF study focuses on the development of a small molecule chemotherapy targeted to CSCs to treat lung cancer. The reviewers had serious reservations about the proposal’s rationale and feasibility, and the research team’s experience with drug development. Thus, reviewers did not recommend this application for funding.