Browsing by Subject "Chemotherapy"
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Item The addition of chemoradiation to lymph node positive gastric cancer is associated with improved overall survival(2019-07) Altman, AriellaBackground: Adjuvant therapies improve survival in gastric cancer; however, the role of adjuvant chemoradiation in the treatment of lymph node (LN)-positive gastric cancer remains uncertain. This study sought to determine the role of adjuvant chemoradiation in addition to chemotherapy after resection for lymph node positive gastric cancer. Methods: The Surveillance, Epidemiology and End Results-Medicare linked data from 2004-2013 was used to identify patients aged 66 and older with LN-positive gastric adenocarcinoma. Multivariable logistic regression evaluated factors associated with receipt of chemoradiation. The Kaplan-Meier method and Cox proportional hazards modeling were used to evaluate overall survival (OS). Results: A total of 2,409 patients with LN-positive gastric adenocarcinoma who underwent upfront surgical resection were identified; 309 (13%) received adjuvant chemotherapy and 407 (17%) received adjuvant chemotherapy and chemoradiation. Among all patients, median OS was 15 months. Median OS was 20 months for patients who received chemotherapy alone and 27 months for patients who received chemotherapy and chemoradiation (p<0.05). Recent diagnosis, older age, tumor stage T3 or T4, and Charleston Comorbidity Index were associated with an increased hazard ratio for death (p<0.05). Receipt of chemoradiation was associated with a decreased hazard ratio for death (p<0.05). Conclusions: In patients with LN-positive gastric adenocarcinoma, the addition of chemoradiation to adjuvant chemotherapy after upfront surgical resection was associated with improved survival irrespective of the extent of lymphadenectomy. These data suggest chemoradiation should be considered in patients with LN-positive gastric adenocarcinoma.Item Association Between Adjuvant Chemotherapy and Nephrotoxicity and Kidney Function Monitoring in Elderly Breast Cancer Patients(2013-05) Li, ShulingBackground: Chronic kidney disease (CKD) and cancer are major public health problems in the elderly population. In elderly cancer patients, little is known about chemotherapy-related nephrotoxicity or patterns of CKD screening. The purpose of this dissertation was to evaluate the association between adjuvant chemotherapy (CHEMO) and risks of acute kidney injury (AKI) and CKD and rate of CKD screening in elderly women diagnosed with stages I-III breast cancer. Methods: The study was a 1:1 individually matched, retrospective cohort design using Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data. Matching was performed at the day of CHEMO initiation based on propensity score. The assembled matched cohorts were used in the analyses for all three objectives with different follow-up periods and statistical methods for each objective. HASH(0x307f974) Results: A total of 28,048 patients were included. CHEMO was associated with a 2.7-fold increased risk of AKI within 6 months after initiation (HR 2.7, 95% CI 1.8-4.1). To find a possible explanation to this association, the distribution of other diseases coded on hospital claims for AKI was examined and showed that septicemia occurred in 40% of CHEMO treated patients with AKI and in only 17% of untreated patients with AKI. No significant association was found between CHEMO and risk of CKD in the maximum 18 years follow-up (HR 1.00, 95% CI 0.93-1.07). The rate of CKD screening after treatment completion was low regardless of CHEMO status. HASH(0x2faf9d4) Conclusion: CHEMO is associated with increased risk of AKI. This association may be partially explained by septicemia caused by infection/neutropenia due to use of myelosuppressive chemotherapeutic agents, which highlights the importance of preventing serious complications of CHEMO in preventing AKI. The finding of no association between CHEMO and risk of CKD may not suggest a late nephrotoxic effect of chemotherapeutic agents commonly used to treat breast cancer in the adjuvant setting, or provide evidence to recommend a clinical practice guideline for CKD screening specifically in elderly breast cancer patients treated with CHEMO. Future studies of CKD as a late effect of cancer treatment for other solid tumors commonly treated with known or potential nephrotoxic agents are warranted.Item Development of Novel Monocarboxylate Transporter Inhibitors as Potential Anticancer Agents(2019-04) Nelson, GradyThe metabolic phenotype of cancer cells is dependent on the differential oxygen and nutrient distribution in the tumor microenvironment. These diminishing resources coupled with increased energetic and biosynthetic demands of tumor cells further encourage the upregulation of glycolysis with overexpression of related enzymes and transporters. This shift towards a more glycolytic character results in a disruption of the intracellular pH as the cell rapidly becomes more acidic. The accumulation of acidic byproducts like lactic acid requires new strategies to maintain cellular homeostasis resulting in the overexpression of transporters. These extracellular acidic byproducts are taken up by neighboring cells and are utilized for oxidative phosphorylation (OxPhos). Cancer cells often switch between glycolysis and OxPhos to meet the energy demands, termed as metabolic plasticity, which is driven by a necessity to avoid conditions that would induce apoptosis. For this reason, cancer cells express proton coupled monocarboxylate transporters 1-4 (MCT1-4). Specifically, these transporters have been found to be expressed in the most aggressive tumors and ultimately been linked to poor patient outcome. Hence, this transporter can be targeted for therapeutic intervention to treat a wide variety of cancers. One well known MCT1 inhibitor α-cyano-4-hydroxycinnamic acid (CHC) has been traditionally used to study the functions of these transporters and it has been found to reduce tumor growth in mouse xenograft models. The therapeutic potential of CHC is hindered by its lack of efficacy at low concentrations and very high dose requirement for significant anticancer efficacy in vivo. In this regard, we have modified the CHC template with alkyl and aryl silyl substitutions and also introduced nitric oxide donors. These structural modifications have resulted novel candidate compounds which exhibit potent MCT1 and MCT4 inhibition and higher cell proliferation inhibition on several cancer cell lines. These drug candidates have also been evaluated for their effects on glycolytic and mitochondrial metabolic parameters. These studies have shown that all the lead derivatives have significant effects on both metabolic processes. Further in vivo preclinical evaluation of lead candidate compounds indicate that these compounds are generally well tolerated in healthy mice and exhibit growth inhibition in MCT1 and MCT4 expressing tumor models.Item Diblock copolymer stabilized nanoparticles for drug delivery via flash nanoprecipitation(2014-10) Han, JingCancer is one of the most challenge diseases to treat around the world. Drug delivery system, as one of the chemotherapeutic treatments has received enorrmous attention from researchers. This thesis is to develop amphiphilic diblock copolymer protected nanoparticles loaded with anti-cancer drug, with small size and high drug loading, to achieve selective drug delivery using EPR effect. Chapter 1 briefly describes the motivation and novelties of this research pursuit. Chapter 2 introduces a modified confined impingement jets mixer with dilution (CIJ-D mixer), using flash nanoprecipitation to produce nanoparticles made of hydrophobic drugs. The CIJ-D mixer was evaluated by the sizes of β-carotene nanoparticles at varied flow conditions compared to these made by multi-inlet vortex mixer. The CIJ-D mixer provides higher efficiency and easiness of handling for nanoparticle preparation. That is why CIJ-D mixer was used for all the work presented in the following chapters. In Chapter 3, we made the first attempt to produce PEG-b-PLGA protected paclitaxel loaded nanoparticles but failed, because paclitaxel is too hydrophilic to be captured in particles. Thus, a series of silicate ester derivatized paclitaxel were synthesized by Hoye research group and successfully encapsulated into nanoparticles. Several nanoparticle post-treatments, such as filtration, hollow fiber diafiltration, and ultracentrifugation were used and assessed, in order to purify nanoparticles. Lyophilization was found to induce nanoparticle aggregation due to the freezing process. The addition of sucrose as cryoprotectant was studied to prevent aggregation and recover nanoparticle. Chapter 4 focuses on developing in vitro drug release protocols, for more accurate quantification of highly hydrophobic paclitaxel prodrugs. Different dialysis devices were used such as dialysis tubes, dialysis cassettes, and dialysis mini capsules. Infinite sink and limited sink conditions were compared as well to provide sufficient concentration gradient across dialysis semi-permeable membrane. At last, a reverse drug release experimental protocol was customized to determine the remaining drug left in dialysis mini capsules while the sink condition was maintained by frequently refreshing buffer solution during in vitro drug release study. Chapter 5 mainly presents the pharmacokinetics of paclitaxel prodrug nanoparticles loaded with different silicate ester derivatives, at different pH, both inside nanoparticles and in buffer solution. Chapter 6 includes a series of Cryo-TEM images of nanoparticles collected at different time, such as fresh nanoparticles immediately after being prepared by CIJ-D mixer, nanoparticles after ultracentrifugation, after lyophilization, 0hr, and 24 hr during drug release study. These images not only showed a reverse liner relation of average particle size and hydrophobicity of the loaded drug, but also displayed a core-shell internal structure of nanoparticles prepared via flash nanoprecipitation and potential particle disassembly after 24hr drug release. Finally, Chapter 7 summarizes the key results and conclusions obtained from previous chapters, lessons learned from mistakes and failures, and future directions for this project, in order to prepare nanoparticles with better controlled size and drug release kinetics and to understand deeply on nanoparticle formation and release mechanisms.Item DNA Modifications As Biomarkers For Precision Medicine In Patients Treated With Alkylating Drugs(2023) Guidolin, ValeriaDNA alkylating drugs have been used as frontline medications to treat cancer for decades. Their chemical reaction with DNA leads to the blockage of DNA replication, which impacts cell replication. While this impacts rapidly dividing cancerous cells, this process is not selective and results in highly variable and oftentimes severe side effects in patients undergoing alkylating-drug based therapies. This observation supports the need for the development of biomarkers able to identify patients who effectively respond to certain therapies and recognize those who instead will develop serious side effects. The use of DNA adducts as predictive biomarkers has been proposed by several studies and herein reviewed. This dissertation focuses on the development and application of analytical methods able to comprehensively screen DNA adducts produced by alkylating drugs. The first study of this dissertation evaluates busulfan reactivity with DNA. Busulfan can promptly react with DNA, therefore, taking advantage of our DNA adductomic approach, DNA adducts formed by reacting busulfan with calf-thymus DNA were characterized. Samples collected from 6 patients undergoing busulfan-based chemotherapy prior to allogeneic hematopoietic cell transplantation were analyzed for the presence of busulfan-derived DNA adducts. Among the 15 adducts detected in vitro, 12 were observed in the patient blood confirming the presence of a large profile of DNA adducts in vivo. Two of the detected adducts were structurally confirmed by comparison with synthetic standards and quantified in patients. Similarly, in the second study, an extensive profile of DNA adducts generated by cyclophosphamide was characterized. Cyclophosphamide is metabolically activated and converted to phosphoramide mustard and acrolein, which are responsible for its efficacy and toxicity. Our DNA adductomic method has been optimized and tailored to maximize the detection of cyclophosphamide-derived adducts. Furthermore, the use of 15N-bacterial DNA served as further confirmation for DNA adduct identification and structural elucidation. This investigation led to the detection of 40 DNA adducts in vitro and 20 DNA adducts in patients treated with cyclophosphamide. The last study focused on the synthesis of a cyclophosphamide-derived DNA adduct to be used for quantitation and as an internal standard for future studies. Departing from reported synthetic schemes, several different approaches were tested. This study is currently ongoing, but the reaction schemes tested allowed for a better understanding of dGuo-alkylation regioselectivity. Overall, the work described in this thesis set the stage for the evaluation of a relationship between busulfan and cyclophosphamide DNA adducts and therapy outcome to identify DNA adducts to be used to stratify patients and distinguish who will benefit from therapies from those who may experience severe adverse toxic outcomes.Item Methotrexate resistance gene transfer in stem cells(2008-11) Gori, Jennifer LeahGene modification of hematopoietic stem cells (HSCs) has the potential to cure genetic, malignant and acquired diseases. Despite success in pre-clinical gene therapy studies, achieving genetic correction or a therapeutic response in humans has been challenging. HIV-1-based lentivirus vectors have come to the forefront of pre-clinical studies due to their ability to more effectively transduce quiescent HSCs. Drug resistance gene expression coupled to chemotherapy after HSC transplantation may support in vivo selection of gene-modified cells while protecting the patient from chemotoxicity. We hypothesized that lentivirus-mediated transfer of a methotrexate (MTX) resistance gene, Tyr22-dihydrofolate reductase (Tyr22-DHFR), into stem cells would support long-term stable gene expression in vivo and protect hematopoietic daughter cells from MTX toxicity. To test our hypothesis, we first generated high-titer lentivirus vectors expressing Tyr22-DHFR and green fluorescent protein (GFP) in different genetic configurations, and then compared MTX resistance, enzyme activity and GFP fluorescence in mouse and human cell lines including human embryonic stem cells (hESCs). Tyr22-DHFR-HSCs protected transplanted mice from MTX myelotoxicity, and conferred a significant survival advantage compared to MTX treated GFP-HSC transplanted mice. To assess the feasibility of a physiologic scale-up in a large animal model, we demonstrated DHFR-GFP expression in canine CD34+ cells and long-term engraftment of gene-modified cells in vivo. MTX administration increased gene-marking in the peripheral blood of one dog, without causing cytopenia. We also defined the optimal priming of HSCs (c-G-CSF/c-SCF BM), transduction conditions and MTX tolerated doses in dogs. Finally, we present a novel application of selective expansion of hESCs-derived cells in mouse xenografts. Methotrexate-resistant (MTXr)-DHFR hESCs gave rise to MTXr-GFP+ teratomas, indicating that that gene-modified cells retain their pluripotency during MTX treatment. MTXr-hESCs placed in stromal cell co-culture differentiated into GFP+ hemato-endothelial cells, including CD34+CD45+ subsets, which subsequently gave rise to MTXr-hematopoietic colony forming cells (CFCs). Finally, we showed that MTX administration of mice bearing hESC xenografts supported in vivo selection of Tyr22-DHFR-hESC-hematopoietic cells and increased engraftment of gene-modified cells in the bone marrow of treated mice. Taken together, these results show that lentivirus vectors effectively transduce MTXr-DHFR into HSCs, thereby preventing life-threatening myelotoxicity (as observed in our mouse studies), and supporting long-term engraftment of gene-modified cells in vivo. These studies mark significant progress of MTX resistance gene therapy toward clinical trials in humans.Item Optimization of Radiation Dosing Schedules(2017-01) Badri, HamidrezaCancer is the second leading cause of death in the United States, claiming the lives of more than half a million people every year. Cancer is aggressively treated with surgery, chemotherapy, and radiotherapy. The primary focus of this thesis is to assist clinicians with hypothesis generation to design novel radiotherapy and chemoradiotherapy fractionation schemes that can improve the results of current clinical practices. We find solutions for some important questions in radiotherapy and chemotherapy fractionation problem. Chapter 2 extends the model developed in the literature to consider radiotherapy fractionated schedules in glioblastomas to best minimize toxicity arising in early- and late-responding tissues. To this end, we decomposed the problem into two separate solvable optimization tasks: optimal radiation schedule or the amount of radiation dose per fraction and optimization of the amount of time that passes between radiation doses. Chapter 3 proposes a method for determining the optimal fractionation in the presence of uncertainties in model parameters. We formulated our problem as a conservative model using robust optimization and a risk adjusted probabilistic formulation. A variable transformation and branch and bound algorithm is implemented to find the optimal regimen. Chapter 4 considers the radiotherapy fractionation problem with a new objective: minimizing production of metastatic cancer cells while keeping normal tissue damage below an acceptable level. A dynamic programming (DP) framework is utilized to determine the optimal fractionation scheme. In Chapter 5, we introduce a mathematical model to obtain optimal drug and radiation protocols in a chemoradiotherapy scheduling problem with two objectives: minimizing metastatic cancer cell populations at multiple potential sites and maintaining a minimum level of control to the primary tumor site. We derive closed-form expressions for optimal chemotherapy fractionation regimens in some special cases. A DP framework is used to determine the optimal radiotherapy fractionation regimen. Using discretization approach, the exact solution of the resulting DP algorithm is computationally intractable. We design efficient DP data structure and use some structural properties of the optimal solution to reduce the complexity of the resulting DP algorithm. In all chapters, we performed substantial numerical experiments to validate our results.Item A phase II trial of carboplatin and docetaxel followed by radiotherapy given in a “Sandwich” method for stage III, IV, and recurrent endometrial cancer.(2010-10) Geller, Melissa Ann MDPurpose: To determine feasibility and efficacy of administering docetaxel and carboplatin chemotherapy followed by pelvic radiotherapy and then consolidation chemotherapy in patients with advanced or recurrent endometrial cancer. Patients and Methods: Patients with surgically staged III-IV (excluding IIIA from positive cytology alone) endometrial cancer or biopsy confirmed recurrent disease were eligible. Treatment consisted of 3 cycles of docetaxel (75mg/m2) and carboplatin (AUC 6) on a q21 day schedule followed by involved field irradiation (45Gy) ± brachytherapy and 3 additional cycles of docetaxel and carboplatin. Kaplan-Meier (KM) methods estimated overall survival (OS) and progression free survival (PFS). Results: Forty-two patients enrolled, 7 did not complete therapy. 95% (39/41) had primary disease. Median age = 58 years (range: 21-81). 78% (32/41) = endometrioid histology. Stages=10 IIIA, 21 IIIC, 1 IVA, 7 IVB, (recurrent=1 IC, 1 IIA). There were 23 non-hematologic and 14 grade 3 and 16 grade 4 hematologic toxicities. Five patients died following treatment with a median follow-up of 16.1 months (range: 5-51). KM estimates and 95% confidence intervals for OS at 1 year were=94.4% (79.5-98.6), at 2 years 90.9% (74.2-97.0)), and at 3 years 79.6% (45.4-93.6). Of the 39 with primary disease, 9 progressed or died within 3 years of study enrollment. KM estimates and 95% confidence intervals for PFS at 1 year were 85.7% (69.0-93.8), at 2 years 75.6% (56.8-87.1), and at 3 years=68.0% (44.6-83.2). Conclusions: “Sandwiching” radiation between chemotherapy for advanced or recurrent endometrial cancer merits further development based on the reported PFS and OS.Item Regulation of Type VII Collagen in Patients with Recessive Dystrophic Epidermolysis Bullosa(2017-08) Vanden Oever, MichaelRecessive Dystrophic Epidermolysis Bullosa (RDEB) is a complex, life-threatening genetic skin disorder with painful complications. Currently, there is no cure, but there have been recent developments in both the basic biological research aspects and the translational therapies which make effectively treating this disease more likely in the near future. These advances include the use of stem cells and gene editing as well as new insights into the molecular mechanisms for certain aspects of RDEB pathology. The overall goals of our lab are to better define and characterize RDEB pathology, develop novel approaches for treating RDEB, and to improve upon the ways in which we analyze and understand the outcomes of those therapies. These goals are inherently dependent upon a comprehensive understanding of how type VII collagen is regulated, both during the normal wound healing process and over the course of therapeutic intervention. To that aim, we set out to understand two aspects of regulation of type VII collagen that were poorly understood: one focused on the nature of type VII collagen regulation during wound healing and the other focused on type VII collagen regulation during the hematopoietic stem cell transplantation process. We identified a particular micro RNA, miR-29, which regulates COL7A1 transcriptionally and post-transcriptionally. We also demonstrated that fludarabine, a key component of the hematopoietic cell transplantation (HCT) preparative regimen, modulates type VII collagen expression during hematopoietic stem cell transplantation. Our studies have identified a novel mechanism of regulation for type VII collagen that will hopefully give valuable insight into how to treat RDEB, ameliorate RDEB pathology, and properly evaluate clinical outcomes in patients that have receive HCT to treat RDEB.Item Translational control of cancer: an exploration of eIF4E and its role in cellular oncogenic transformation.(2009-04) Underwood II, Jon MichaelCancer is currently the 2nd leading cause of death in the U.S., responsible for approximately one quarter of the annual death rate. While cancer is genetically diverse, we suspect there may be common components of the cellular machinery where oncogenic signals converge, and that these critical regulatory nodes may represent molecular targets for new therapies. My approach derives from recent work on human breast and lung carcinoma, and murine models of lymphoid malignancies; which identify the cap-dependent protein synthesis machinery as a critical point of convergence and amplification of oncogenic signals emanating from the Ras/PI3K/Akt cascade. The rate limiting step in protein synthesis is initiation, mediated by the trimeric protein eukaryotic initiation factor 4F (eIF4F). The limiting component of eIF4F is the mRNA cap-binding protein, eukaryotic initiation factor 4E (eIF4E). Over expression of eIF4E transforms immortalized rodent fibroblasts and confers primary human cells with several cancer-related functions including decreased growth factor requirement for proliferation and survival, colony formation and anchorage independence. However, until very recently all experiments examining the oncogenic potential of eIF4E have involved constitutive over expression in stably transfected cell lines; leaving uncertain precisely which oncogenic functions could be ascribed directly to eIF4E, and which relate to its ability to suppress apoptosis - thus creating a permissive environment for subsequent oncogenic mutations. I have developed a high fidelity eIF4E inducible system which allows me to abruptly activate eIF4E over expression. With this system I am able to establish a direct connection between eIF4E induction and autonomous cell proliferation. I have also been able to specify the cell cycle kinetics which occurs after eIF4E induction, including the ability of eIF4E to bypass growth factor initiation on the canonical proliferative pathway. The growth factor bypass properties of eIF4E are due to its ability to translationally activate cyclin D1, an occurrence I report for the first time. I also demonstrate the potential of pharmacological intervention targeting hyperactive translational activity. With the use of small molecular compounds which antagonize translation initiation, I demonstrate the ability to reverse eIF4E triggered proliferation in the eIF4E inducible system and the selective elimination of cancer cells with minimal toxicity in normal cells. This study has lead to a better understanding of how cap-dependent translation regulates cell proliferation and advanced the novel concept for cancer biology and therapeutics focused on translational control.