2017 — 2021 |
Krishnan, Sunil Lin, Steven Hsesheng |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Enhancing Chemoradiation Efficacy Through Unbiased Drug Discovery Approaches @ University of Tx Md Anderson Can Ctr
A major barrier to improving cure rates in locally advanced cancers is our inability to make progress beyond what chemoradiation (CRT) can currently deliver. Combination strategies using molecular targeted therapies with CRT hold promise for improving outcomes further. While many drugs could enhance the effects of radiation alone, we have discovered that the effects are quite unpredictable when drugs are combined with chemotherapy and radiotherapy. The successful translation of adding molecular targeted agents to CRT would require an understanding of the molecular pathways that enable the cancer cell to survive under conditions of CRT. Inhibiting these pathways with molecular targeted drugs will be synergistic with CRT in the cancer-specific context. Using a set of molecular targeted drugs from the CTEP portfolio as an initial starting point, we will investigate two hard-to-treat cancer types treated with CRT, non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC). We will identify drugs that could synergize with radiation and CRT using a high throughput clonogenic survival screen that we have developed on validated cancer lines and then test the most clinically promising combinations of agents to multiple cell lines with varying genetic backgrounds, first in vitro and then further validated using 2 in vivo models: a panel of patient-derived xenografts (PDXs) and orthotopic tumor models using syngeneic tumors, all done in combination with clinically-relevant chemotherapies. The pharmacokinetic and pharmacodynamic properties of these drugs with chemotherapy in animals and tumors will be assessed in order to determine the optimal sequencing approach with conventionally fractionated radiotherapy. Since we have discovered that chemotherapy significantly alters the response of cancer cells to radiation and targeted drugs, we will also evaluate the molecular mechanisms that explain the response to CRT, and identify potential factors that may influence this response using 4 major approaches. In the first more classic approach, we will assess DNA damage repair pathways and reactive oxygen species generation when targeted agents are combined with radiation or CRT. Second, we will use reverse phase protein arrays (RPPA) to assess the functional proteome to determine pathways that may be altered with molecular targeted drugs in the setting of RT or CRT. In the third approach, we will use Stable Isotope Labeling with Amino Acids (SILAC) to assess global proteomic and phosphoproteomic changes that occur with radiation and CRT treatment, and how these pathways could be altered with specific molecular targeted therapies. Lastly, we will use Imaging Mass Spectrometry to analyze drug distribution within the various tumor models and assess how the pharmacodynamic heterogeneity impacts CRT responsiveness. Our proposal will not only identify the most promising drugs that could best be combined with CRT in NSCLC and PDAC, but we will have identified molecular and tumor factors that confer drug resistance which will enable future development of novel targeted strategies to enhance CRT or appropriately select patient for personalized therapy. Our approach will generate the high quality preclinical data and novel insights to fulfill the overall FOA objective, which is ?to accelerate the pace at which combined modality treatments with greater efficacy are identified and incorporated into standard practices for treatments?.
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0.914 |
2019 — 2021 |
Al-Atrash, Gheath (co-PI) [⬀] Lin, Steven Hsesheng |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Mitigating High Grade Radiation-Induced Lymphopenia Through Pretreatment Autologous Lymphocyte Infusion @ University of Tx Md Anderson Can Ctr
PROJECT SUMMARY Radiation induced lymphopenia (RIL) is a common radiation-related toxicity that has been recognized for over a century but often ignored as clinically inconsequential. However, accumulating evidence has demonstrated strong association of high grade RIL (seen in 30-50% of patients) with poor prognosis. The pervasive role of radiotherapy in the curative management of solid tumors supports the need to develop mitigating strategies, particularly for patients with a high risk of developing grade 4 (G4) RIL. We have compelling evidence from both clinical and preclinical work that severe RIL impacts cancer control and therapy effectiveness, and methods to reduce RIL may improve treatment outcomes. To further develop these approaches for clinical translation, we have proposed 2 specific aims. In aim 1, we will build on our initial prediction model for G4 RIL and leverage our large database of esophageal cancer patients who have completed chemoradiation (CRT) to develop a better predictive model for G4 RIL so that we can rapidly and efficiently identify the highest risk patients for mitigating strategies. In aim 2, we will determine the feasibility and safety of raising the baseline lymphocyte levels by autologous lymphocyte infusion (ALI) prior to initiating CRT. Fundamentally, this research will allow us to develop the necessary computational tool capable of properly identifying patients at risk for developing severe RIL, and complete a small feasibility and safety study of using ALI as a way to raise the baseline pre-treatment lymphocyte levels so that the probability of developing G4 RIL could be possibly curtailed. By targeting the at-risk patients to receive RIL mitigating strategies, we will hopefully be able to improve the cancer outcomes of standard cancer therapies, and build on current innovative strategies of immunotherapy and radiation combinations.
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0.914 |
2019 — 2020 |
Lin, Steven Hsesheng |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Targeting Tankyrases to Mitigate Immunosuppression and Enhance Cancer Immunotherapy @ University of Tx Md Anderson Can Ctr
PROJECT SUMMARY Liver kinase B1 (LKB1) is a key regulator of cellular energy homeostasis and well known tumor suppressor gene in many cancers, particularly lung cancer, where it is deleted in ~30 percent of tumors. LKB1 suppression or depletion leads to enhanced tumorigenesis, increased immunosuppression, and reduced response to immune checkpoint inhibitors. Despite the importance of LKB1 negative regulation on tumor growth and aggressiveness, there is no known upstream regulator of LKB1. Through a rationally designed drug screen, we identified tankyrases (TNKS; TNKS1, or PARP5A, and TNKS2, or PARP5B), as upstream negative regulators of LKB1. TNKS belong to the closely related members of the poly (ADP-ribose) polymerase (PARP) family that adds ADP-ribose moieties to target proteins using ?-NAD+ as substrate, termed PARsylation. PARsylation of target proteins by TNKS typically leads to ubiquination and proteasome degradation, such as AXIN (which sequesters APC/?-catenin in Wnt signaling), PTEN, and telomerase. However, PARsylation of LKB1 does not lead to LKB1 degradation, but inhibit LKB1 activity. Overexpression of TNKS stimulates tumor cellular proliferation in vitro and enhances tumorigenesis in vivo that is LKB1-dependent. Lung tumors (both adenocarcinoma and squamous cell carcinoma) that overexpress TNKS1 in LKB1 expressing tumors portended to poorer prognosis. Given the fact that LKB1 mutant lung tumors are immune suppressed and respond poorly to immune checkpoint inhibitors, we hypothesize that TNKS potentially could be the negative regulator of LKB1 that induce immune suppression in LKB1 wild type tumors. We will test our hypothesis by: (1) determining the role of TNKS on conferring immunosuppression in the tumor microenvironment through the use of syngeneic orthotopic models and Genetically-Engineered Mouse Models (GEMMs) to better understand if TNKS levels confers immunosuppressive state in tumors; and (2) utilizing syngeneic orthotopic tumor models to evaluate the ability of TNKS expression to generate resistance to immunotherapy and determine the effectiveness of TNKS inhibition on enhancing immunotherapy response. Upon completion of this project, we will have a clearer understanding of the immunosuppressive state that is conferred by TNKS through the negative regulation of LKB1. This research will implicate TNKS as a target for clinical translation to improve current therapies in lung cancer.
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0.914 |