Lung carcinoma is one of the leading causes of cancer deaths in the world. Treatment for early stage non small cell lung cancer (NSCLC) is surgery while chemotherapy is the mainstay of treatment in small cell lung cancer (SCLC). Most veterans present as locally advanced or metastatic disease which makes resection not possible. For these patients, cisplatin or its less nephrotoxic analog carboplatin is the main chemotherapeutic drug used for both NSCLC and SCLC. The majority of lung cancer patients will respond initially to cisplatin treatment; however, development of drug resistance is inevitable which results in disease progression. Thus, development of a new strategy to treat cisplatin resistant lung cancer will undoubtedly have a major impact for the treatment of these patients. Although there are overwhelming publications in the past decade on cisplatin resistance, but thus far no drugs are available which could reverse cisplatin resistance or selectively kill these resistant cells. We have discovered novel biochemical changes in cisplatin resistant cells which can be utilized as targets to selectively eradicate them. Firstly, we have found that all cisplatin resistant cells lines including primary culture from patients possess higher reactive oxygen species (ROS) levels when compared to normal cells or their parental cell counterparts. Consequently, agents which increase ROS such as elesclomol can push them beyond their tolerance limit which ultimately leads to cell death. Secondly, these cisplatin resistant cells have decreased intracellular thioredoxin-1 (TRX1) levels as a result of increasing secretion under in vitro and in vivo conditions which could be a primary contributory factor to higher ROS levels. Thirdly, cisplatin resistant cells are no longer dependent on glycolysis metabolism, but rely on amino acids and/or fatty acids (oxidative metabolism) as their carbon skeleton source. Significantly, glutamine deprivation or inhibition of key enzyme in fatty acid synthetic pathway can selectively kill cisplatin resistant cells. Taken together, we hypothesize that decreased intracellular TRX1, which results in higher ROS accumulation, could lead to metabolic reprogramming in cisplatin resistant tumors. In this application, we plan to further confirm and exploit these findings by (i) determine that cisplatin resistant lung cancer cells switch from glycolytic metabolism to oxidative metabolism as their main carbon source for energy and biosynthesis, (ii) investigate that TRX1 is a key factor in ROS accumulation, cisplatin sensitivity, and alteration in tumor metabolism, (iii) determine that ROS generation agent or metabolic inhibitor which can selectively kill cisplatin resistant cells in vitro also occurs in vivo, (iv) determine the possible relationships between ROS, TRX1, and changes in tumor metabolism are also found in tumor samples obtained from patients who have failed cisplatin treatment. To further evaluate the clinical relevance of our findings, we will confirm that a ROS producing agent or metabolic inhibitor is also highly cytotoxic to freshly isolated cisplatin resistant lung cancer cells from patients. Overall, this proposed work will sere as a novel approach to overcome cisplatin resistance by exploiting the primary biochemical differences which these resistant cells adopt to survive. Thus, by targeting these differences, we can selectively eradicate these resistant cells with minimal normal tissue toxicity. Furthermore, the findings obtained from this application can also be used as a platform to investigate possible ways to selectively kill cisplatin resistant cells from other tumor types.

Public Health Relevance

Lung cancer is one of the leading causes of death in the world. While early stage lung cancer can be treated by surgical resection, chemotherapy remains the mainstay for treatment for locally advanced and metastatic disease. Cisplatin or its analog carboplatin is one of the main drugs which has been utilized for the treatment of both small cell and non small cell lung cancer. Development of platinum resistance is inevitable and hinders the likelihood of achieving remission and hence leads to poor survival. We have found that all cisplatin resistant lung cancer cells express higher baseline levels of oxidative stress. Moreover, these resistant cells appear to change their metabolic pathway in order to adapt to survive under high oxidative stress condition. By identifying and targeting this pathway, cisplatin resistant cells can be selectively killed. The knowledge gained from this proposed work will help to improve treatment outcome and survival in these patients.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (IK2)
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Oncology A (ONCA)
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Miami VA Health Care System
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