Unresectable locally advanced non-small cell lung cancer treated with concurrent platinum-based chemotherapy and thoracic radiation results in primary tumor recurrence in >35-80% of cases from radioresistant tumors. Therefore, research aimed at understanding mechanisms of radioresistance and strategies to overcome this problem are paramount to better lung cancer treatment outcomes. We found TWIST1 was commonly overexpressed in human lung cancers and Twist1 could confer radiation resistance to lung epithelial cells, lung cancer cells and autochthonous mouse lung tumors in vivo. Twist1 is a basic helix- loop-helix transcriptional factor. The domains of Twist1 and transcriptional targets of Twist1 that are required for radioresistance are unknown. In order to maximize the therapeutic potential of inhibiting Twist1 for lung cancer, we must precisely define the protein domains of Twist1 and/or the downstream transcriptional targets of Twist1 required for radioresistance. In the present proposal we have three specific aims to test two hypotheses that will provide more mechanistic insight into the structure-function relationships of Twist1 and lung cancer radioresistance. One central hypothesis of this proposal is that specific protein domains of Twist1 are required for radioresistance. We have developed a novel lung epithelium specific Twist1 mouse model and various mutant versions of Twist1 to facilitate these studies. Our second testable hypothesis is there is a defined set of """"""""core"""""""" transcriptional targets of Twist1 required for radioresistance. The studies outlined in our proposal will provide valuable knowledge to the pathophysiologic role of Twist1 in lung cancer and Twist1- induced radioresistance. Finally, validating a novel preclinical inducible lung cancer model of radioresistance will create a model to test new treatments for this fatal disease in combination with radiation.
Specific Aim #1 : Characterize the domains of Twist1 required for radioresistance in vitro. We will use mouse embryo fibroblasts (MEFs) and isogenic human lung cancer cells expressing Twist1 and Twist1 mutants to examine which domains of Twist1 are necessary for a radioresistant phenotype. We will determine the cell autonomous mechanisms of Twist1-induced radioresistance in vitro.
Specific Aim #2 : Characterize the domains of Twist1 required for radioresistance of KrasG12D-induced autochthonous lung tumors. We will test this hypothesis with serial non-invasive imaging and confirm our findings with standard molecular-histologic methods to follow the response to radiation in our novel Twist1 transgenic lung tumor model. We will also examine the dominant mechanisms for Twist1-dependent radiation response modulation in vivo.
Specific Aim #3 : Determine Twist1 transcriptional targets correlated with Twist1-induced radioresistance using gene expression and ChIP-chip profiling. We will use integrative genome-wide bioinformatic approaches on MEFs and human lung cancer cells to isolate the """"""""core"""""""" gene targets required for Twist1-induced radioresistance.
The work we have proposed has a direct impact on the etiology and potential treatment of locally advanced lung cancer. As Twist1 is not typically expressed post-natally, therapies directed against Twist1 may be a more specific and perhaps less toxic therapy. Lastly, the study of Twist1 and EMT will allow a broader understanding of radioresistance in other tissues and may expose a new pathway to target radioresistance in general.
|Narang, A K; Trieu, J; Radwan, N et al. (2017) End-of-radiation PSA as a novel prognostic factor in patients undergoing definitive radiation and androgen deprivation therapy for prostate cancer. Prostate Cancer Prostatic Dis 20:203-209|
|Malek, Reem; Wang, Hailun; Taparra, Kekoa et al. (2017) Therapeutic Targeting of Epithelial Plasticity Programs: Focus on the Epithelial-Mesenchymal Transition. Cells Tissues Organs 203:114-127|
|Barbhuiya, Mustafa A; Mirando, Adam C; Simons, Brian W et al. (2017) Therapeutic potential of an anti-angiogenic multimodal biomimetic peptide in hepatocellular carcinoma. Oncotarget 8:101520-101534|
|Malek, Reem; Gajula, Rajendra P; Williams, Russell D et al. (2017) TWIST1-WDR5-Hottip Regulates Hoxa9 Chromatin to Facilitate Prostate Cancer Metastasis. Cancer Res 77:3181-3193|
|Tran, Phuoc T; Antonarakis, Emmanuel S (2017) Altering the Natural History of Oligometastatic Prostate Cancer With Local Therapies: Reality Versus Illusion. J Oncol Pract 13:21-24|
|Yochum, Zachary A; Cades, Jessica; Mazzacurati, Lucia et al. (2017) A First-in-Class TWIST1 Inhibitor with Activity in Oncogene-Driven Lung Cancer. Mol Cancer Res 15:1764-1776|
|Rimar, Kalen J; Tran, Phuoc T; Matulewicz, Richard S et al. (2017) The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies. Cancer 123:1912-1924|
|Ross, A E; Den, R B; Yousefi, K et al. (2016) Efficacy of post-operative radiation in a prostatectomy cohort adjusted for clinical and genomic risk. Prostate Cancer Prostatic Dis 19:277-82|
|Narang, Amol K; Tran, Phuoc T (2016) Prostate cancer: Case volume and improved outcomes across cancer care. Nat Rev Urol 13:186-7|
|Narang, Amol K; Gergis, Carol; Robertson, Scott P et al. (2016) Very High-Risk Localized Prostate Cancer: Outcomes Following Definitive Radiation. Int J Radiat Oncol Biol Phys 94:254-62|
Showing the most recent 10 out of 43 publications