Browsing by Subject "Antineoplastic Agents"
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Item Anti-Angiogenic Therapy in Non-Small Cell Lung Cancer: Characterizing a New Therapy and Investigating Potential Mechanisms of Resistance(2012-07-20) Sullivan, Laura Anne; Brekken, Rolf A.Angiogenesis is the development of blood vessels from a pre-existing vascular network. This process is essential during growth, development and wound healing and plays a critical role in the growth and progression of cancer. Initial tumor size is restricted by the diffusion capacity of oxygen and nutrients from surrounding blood vessels. Therefore, to progress beyond a volume of several millimeters, a tumor must stimulate angiogenesis to generate a vascular network that will supply the tumor with the necessary blood, oxygen and nutrients that will allow for continued growth, invasion and metastasis. Over forty years ago, Judah Folkman hypothesized that targeting tumor angiogenesis would be beneficial for cancer patients. One of the first targets for this new class of drugs was vascular endothelial growth factor (VEGF) a predominant mediator of physiological and pathological angiogenesis. Bevacizumab (Avastin®, Genentech/Roche), a humanized monoclonal antibody that recognizes human VEGF and blocks VEGF from binding to VEGF receptor (VEGFR) 1 and 2, was the first anti-angiogenic drug approved by the United States Food and Drug Administration for the treatment of cancer and remains the gold standard for this class of therapeutics. The Brekken laboratory, in collaborations with Peregrine Pharmaceuticals and Affitech A/S has generated a fully human monoclonal antibody, r84 that recognizes mouse and human VEGF and blocks VEGF binding only to VEGFR2. The data presented in the first half of this dissertation demonstrate the specificity of r84 for VEGF in vitro and in vivo, the efficacy of r84 to control tumor growth and the superior safety profile of r84 as compared to bevacizumab. Although anti-angiogenic therapy was highly anticipated to have great success in patients, overall results have been somewhat disappointing with modest improvements in patient progression free survival and few improvements to overall survival. In addition, with the expanding use of anti-angiogenic drugs such as bevacizumab and a host of receptor tyrosine kinase inhibitors in the clinic, it is becoming increasingly apparent that not all tumors respond or maintain sensitivity to treatment. Therefore, it is increasingly important to identify mechanisms of resistance to anti-angiogenic therapy so that new drug targets can be identified and/or patients can be appropriately screened for markers that can predict for resistance or sensitivity to anti-angiogenic therapy de novo. Non-small cell lung cancer (NSCLC), the most common form of lung cancer, claims the most new diagnoses and cancer-related deaths than any other cancer worldwide and the therapeutic options currently available for this disease, including bevacizumab have done little to change this statistic. The latter half of this thesis focuses on the in vivo screening of human NSCLC cell lines to identify mechanisms of resistance to the anti-angiogenic monoclonal antibodies bevacizumab and r84 in non-small cell lung cancer.Item Antiviral chemotherapy(1989-02-02) Luby, James P.Item The biological therapy of breast cancer: Molecular targets and monoclonal antibodies HER2 and herceptin(2003-05-08) Haley, Barbara B.Item Biosimilars in oncology(2020-01-24) Unni, NishaItem Challenges for chronic myelogenous leukemia therapy in the post-imatinib era: A kinase strikes back(2004-07-01) Ilaria, Robert L., Jr.Item Chimeric ANTI-CD19 Monoclonal Antibodies for the Treatment of Precursor B Cell Acute Lymphoblastic Leukemia(2009-09-04) Tsai, Lydia Kar-Yuk; Vitetta, Ellen S.Thousands of people are diagnosed with B cell malignancies every year, yet the only FDA-approved immunotherapies for them are based on anti-CD20 monoclonal antibodies (MAbs). However, CD20 is not expressed on precursor B cell acute lymphoblastic leukemia (pre-B ALL), and CD20 expression is often lost following anti-CD20 immunotherapy. CD19 is a pan B cell membrane antigen that is restricted to the B cell lineage and expressed on B cell lymphomas and pre-B ALLs. Previous studies have shown that a murine anti-human CD19 MAb, HD37, has efficacy in SCID mice with human B cell tumors. Furthermore, homodimers consisting of two conjugated IgG molecules of HD37 are more effective than monomers at inducing tumor cell death. Yet, their large size prevents effective tumor penetration, and normal Fc effector funtions are often not retained. Murine antibodies are also highly immunogenic. Therefore, the objective of this study was to construct, express, and test the in vitro and in vivo activities of chimeric divalent and tetravalent HD37 MAbs. Both chimeric HD37 MAbs and the murine HD37 MAb were equally effective at mediating antibody dependent cellular cytotoxicity (ADCC) with mouse effector cells. The anti-tumor activities of all three MAbs were identical in SCID mice xenografted with human B cell tumors. However, the chimeric tetravalent MAb has a higher binding affinity and a longer half-life of dissociation than either of the divalent MAbs. Moreover, the chimeric tetravalent MAb mediated ADCC and complement dependent cytotoxicty (CDC) more efficiently than the divalent MAbs when human effector cells and human complement were used. None of the MAbs were cytotoxic to target cells in the absence of effector cells or complement. These data suggest that 1) the HD37 MAbs effectively extend the mean survival time of SCID mice engrafted with human B cell tumors; 2) more than two of the tetravalent HD37 MAb's binding sites are active; and 3) because in vitro results show that the chimeric tetravalent MAb is more effective than the divalent MAbs at mediating ADCC and CDC with human effector cells and complement, the chimeric tetravalent HD37 MAb could be superior to the divalent MAbs in humans.Item A Cytokine Receptor Masked IL-2 Prodrug Selectively Activates Tumor-Infiltrating Lymphocytes for Potent Antitumor Therapy(August 2021) Hsu, Eric Jonathan; Zhang, Chengcheng "Alec"; Farrar, J. David; Malladi, Srinivas; Yan, Nan; Fu, Yang-XinCancers are very difficult to treat, and many cancer patients fail to respond to numerous standard of care therapies. Many of these tumors have been observed to lack functional CD8 T cells, which have been observed to be correlated with improved patient prognosis. One of the main strategies to combat the lack of functional tumor infiltrating immune cells is to treat patients with immune stimulating cytokines such as interleukin-2 (IL-2). As a potent lymphocyte activator, IL-2 is an FDA approved treatment for multiple metastatic cancers. However, its clinical use is limited by short half-life, low potency, and severe in vivo toxicity. Current IL-2 engineering strategies exhibit evidence of peripheral cytotoxicity. Here, limitations of both recombinant IL-2 and these next generation IL-2 variants are addressed through the engineering of a novel IL-2 prodrug (ProIL2). Numerous designs of ProIL2 were designed, engineered, and tested until a final optimal construct was synthesized. The activity of a CD8 T cell-preferential IL-2 mutein/Fc fusion protein is masked with IL2 receptor beta linked to a tumor-associated protease substrate. ProIL2 restores activity after cleavage by tumor-associated enzymes, and preferentially activates inside tumors, where it expands antigen-specific CD8 T cells. This significantly reduces IL-2 toxicity and mortality without compromising antitumor efficacy. ProIL2 also overcomes resistance of cancers to immune checkpoint blockade. Furthermore, neoadjuvant ProIL2 treatment can eliminate metastatic cancer through an abscopal effect. Lastly, ProIL2 can also synergize with radiation therapy to more effectively control both primary and metastatic cancer. Further protein engineering strategies are being implemented to overcome potential limitations of ProIL2. Taken together, this approach presents an effective tumor targeting therapy with reduced toxicity.Item Development of a Lung Cancer Targeting Peptide for Imaging and Drug Delivery(2018-04-12) Allred, Curtis Arlin; Corbin, Ian R.; Brown, Kathlynn C.; Kohler, Jennifer J.; Minna, John D.Lung cancer kills more people in the United Stated than the next three biggest cancer killers combined. Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer patients and has an overall estimated 5-year survival of 18% in 2017. The emergence of targeted therapies (molecularly guided treatment) has improved the overall survival and quality of life of ~20% of NSCLC patients. A different molecularly guided treatment modality, targeting therapy, has shown success in other cancer types, but has not yet been successfully applied in NSCLC. Peptides are a class of molecules that have demonstrated exquisite targeting of cancer cells. HCC15.2 peptide was identified from a phage display library screen on NSCLC cells. It binds to an unknown receptor on a specific subset of NSCLC patient samples (24%) and cell lines (50%), which is not present in immortalized but non-transformed human bronchial epithelial cells (HBEC). Not only does HCC15.2 have a high affinity of ~5 nM and high specificity, it also triggers internalization and delivers its cargo into the cancer cell. HCC15.2 was optimized by altering the multimerization and amino acid content and protecting it from serum degradation. After the optimizations, HCC15.2 was shown to deliver many cargo types into cancer cells which traffic to and accumulate in lysosomes. HCC15.2 also demonstrated its ability to home to a subcutaneous xenograft in mice ~30-fold better than non-targeted dye after systemic delivery. This peptide used in molecular imaging could aid in earlier tumor detection, which correlates with better patient survival. HCC15.2 conjugated to saporin, a ribosome inactivating protein, showed an IC50 of 5.4 nM in in vitro viability assays. Delivery of saporin by HCC15.2 significantly slowed the growth of tumor xenografts. HCC15.2 is a perfect candidate for molecularly guided imaging and therapy.Item EGFR and Akt Signaling in Rhabdomyosarcoma Pathogenesis(2018-07-25) Granados, Valerie Ann; Amatruda, James F.; Olson, Eric N.; Lum, Lawrence; Galindo, ReneRhabdomyosarcoma is an aggressive soft-tissue malignancy comprised microscopically of neoplastic skeletal muscle-lineage precursors that fail to exit the cell-cycle and fuse into syncytial muscle - the underlying pathogenetic mechanisms for which remain unclear. We previously identified that misregulated myoblast fusion signaling via the TANC1 adaptor molecule promotes neoplastic transformation in RMS cells. As TANC1 is not presently pharmacologically targetable, here we have turned to our Drosophila RMS-related model to identify myoblast fusion-related elements potentially targetable in RMS. Genetic modifier screening against the fly model revealed that decreased Epidermal Growth Factor Receptor (EGFR) activity, which regulates myoblast fusion programming in flies, suppresses PAX-FOXO1 (PF)-induced lethality. As EGFR is pharmacologically targetable, we demonstrate that EGFR inhibitors antagonize RMS in a ERMS-RD cell line, but that other RMS cell lines are resistant. Further interrogation finds that EGFR inhibitor-sensitive cells exhibit marked down-regulated activation of the Akt intracellular signaling transducer, but not MEK/MAPK or STAT3, suggesting that Akt promotes and/or sustains RMS. We then demonstrate that Akt pharmacologic inhibition antagonizes RMS in vitro and in vivo, including RMS cells resistant to EGFR inhibition. We additionally find that sustained Akt1 activity promotes RMS cell terminal differentiation-arrest. Together, these findings point towards Akt activity as a broad RMS underpinning and therapeutic vulnerability.Item Elucidating the Target and Selectivity of a Non-Small Cell Lung Cancer Toxin(2019-07-11) Madhusudhan, Nikhil; Tu, Benjamin; Nijhawan, Deepak; DeBerardinis, Ralph J.; McFadden, David G.; Mishra, PrashantSelective toxicity among cancer cells of the same lineage is a hallmark of targeted therapies, and so identifying compounds that impair proliferation selectively is an important strategy in drug development. Here, we report the discovery of the quinazoline dione compound (QDC), a molecule that exhibits selective toxicity across 100 non-small cell lung cancer (NSCLC) lines. Using photoreactive probes, we found that the QDC targets mitochondrial Complex I. We investigated the selective toxicity of Complex I inhibition across NSCLC and found that a high baseline content of aspartate formed via reductive glutamine metabolism promotes resistance to mitochondrial inhibition. Altered metabolism is an important feature of cancer and there is significant interest in understanding how differences in tumor metabolism can be exploited for therapy. NSCLC cells subject to mitochondrial inhibition use reductive carboxylation to meet aspartate demand, which suggests that targeting reductive aspartate synthesis would enhance clinical response to Complex I inhibitors.Item Elucidation of the Mechanism of Action of a Cell Line Selective Toxin(2019-01-31) Theodoropoulos, Panayotis Christos; Yu, Hongtao; Nijhawan, Deepak; Brown, Michael S.; Ready, Joseph M.; Chen, Zhijian J.A hallmark of targeted cancer therapies is selective toxicity among cancer cell lines. We evaluated results from a viability screen of over 200,000 small molecules to identify two chemical series, oxalamides and benzothiazoles, that were selectively toxic to the same four of 12 lung cancer cell lines at low nanomolar concentrations. Sensitive cell lines expressed cytochrome P450 (CYP) 4F11, which metabolized the compounds into irreversible stearoyl CoA desaturase (SCD) inhibitors. SCD has been recognized as a promising biological target in cancer and metabolic disease. However, SCD is essential to sebocytes, and accordingly SCD inhibitors cause skin toxicity. Mouse sebocytes were unable to activate the benzothiazoles or oxalamides into SCD inhibitors, providing a therapeutic window for inhibiting SCD in vivo. We thus offer a strategy to target SCD in cancer by taking advantage of high CYP expression in a subset of tumors.Item The Emergence of Diverse Drug-Resistance Mechanisms from Drug Tolerant Cancer Persister Cells(2015-08-31) Ramirez, Michael Edward; Mendell, Joshua T.; Shay, Jerry W.; Cobb, Melanie H.; Altschuler, Steven J.; Wu, Lani; Wu, Jiang I.Cancer therapy has traditionally focused on eliminating fast-growing populations of cells, yet a growing body of evidence suggests that small subpopulations of cancer cells can evade strong selective drug pressure by entering a slow-growing "persister" state. This drug-tolerant state has been hypothesized to be part of an initial strategy towards eventual acquisition of bona fide drug-resistance mechanisms. However, the diversity and clinical relevance of drug-resistance mechanisms that can expand from a persister bottleneck is unknown. Here, we compared persister-derived, erlotinib-resistant colonies that arose from a single, EGFR-addicted lung cancer cell. We found, using a combination of large-scale drug screening and whole-exome sequencing, that our erlotinib-resistant colonies had acquired diverse resistance mechanisms, including the most commonly observed clinical resistance mechanisms. Thus, the drug-tolerant persister state does not limit--and may even provide a latent reservoir of cells--from which drug-resistance heterogeneity can emerge.Item Enantioselective Total Synthesis of the Kibdelones(2012-07-20) Butler, John R.; Ready, Joseph M.The kibdelones are a family of aromatic polyketides reported in 2006 by Capon and co-workers. These compounds possess potent antibiotic and cytotoxic activities and operate via an unknown and potentially unique mode of action. In order to fully investigate these properties the kibdelones were targeted for total synthesis. Novel methods for heterocycle synthesis and biaryl bond formation were also targeted as part of the synthesis. The kibdelones contain a chlorinated isoquinolinone and stereogenically rich tetrahydroxanthone heterocycles, which make them challenging synthetic targets. To synthesize these compounds a convergent strategy has been developed that splits the molecule into two fragments of similar size. The isoquinolinone moiety was synthesized from amino acid and benzoic acid fragments using a Pomeranz-Fritsch reaction. Our approach to synthesize the tetrahydroxanthone fragment took advantage of an element of latent C2 symmetry present in the kibdelones. Using the Shi-epoxidation this fragment was synthesized in an enantioselective fashion from resorcinol. After joining these fragments with sequential Sonogashira reactions a demanding late stage C-H arylation reaction was used to forge the final C-C bond of the natural product. Importantly, this biaryl bond formation was enabled by the serendipitous discovery of a selective copper-catalyzed iodination reaction. All of these efforts led to the successful 20-step synthesis of (-)-kibdelone C, setting the stage for further biological enquiry of these exciting natural products.Item Ethical use of surrogate measures in accelerated approval: aducanumab and beyond(2022-01-11) Kesselheim, Aaron S.[Note: The slide presentation is not available from this event.] The accelerated approval pathway was designed in the wake of the HIV epidemic to provide a pathway for drugs to reach the market based on showing changes to not-fully-validated surrogate measures. Since then, it has largely been applied to cancer drugs, and became the center of substantial attention with the June 2021 approval of aducanumab for Alzheimer's disease. We will review the ethical tensions at issue in approving drugs based on unproven surrogate measures, and consider how the accelerated approval pathway has been implemented.Item Immune checkpoint inhibitor related endocrinopathies(2018-10-26) Ali, SadiaItem Immunotherapy in lung cancer treatment: a new paradigm still in revision(2019-10-11) Kim, JamesItem Macrophage PPAR-Gamma Inhibits Gpr132 to Mediate the Anti-Tumor Effects of Rosiglitazone(2016-04-04) Cheng, Wing Yin; Brekken, Rolf A.; Wan, Yihong; Minna, John D.; Pearson, Gray W.Tumor-associated macrophage (TAM) significantly contributes to tumorigenesis. Human cancer is enhanced by PPARgamma loss-of-function mutations, and inhibited by the thiazolidinedione (TZD) class of synthetic PPARgamma agonists and type 2 diabetes drugs such as rosiglitazone. However, it remains enigmatic whether and how macrophage contributes to PPARgamma tumor-suppressive functions. Here we uncover that macrophage PPARgamma deletion in mice exacerbates mammary tumor development by increasing the number and pro-inflammatory property of TAMs, which in turn stimulate cancer cell proliferation. Macrophage PPARgamma loss also impairs the anti-tumor effects of rosiglitazone. Mechanistically, we identify Gpr132 as a novel direct PPARgamma target in macrophage whose expression is enhanced by PPARgamma loss but repressed by PPARgamma activation. Functionally, macrophage Gpr132 is pro-inflammatory and protumor. Genetic Gpr132 deletion not only retards inflammation and cancer growth but also abrogates the anti-tumor effects of PPARgamma and rosiglitazone. Pharmacological Gpr132 inhibition significantly impedes mammary tumor malignancy. These findings identify macrophage PPARgamma and Gpr132 as critical TAM modulators, new cancer therapeutic targets, and essential mediators of TZD anti-cancer effects.Item Metabolic Diversity in Human Non-Small Cell Lung Cancer Cells(2015-10-01) Chen, Pei-Hsuan; Garcia, Joseph A.; DeBerardinis, Ralph J.; Minna, John D.; White, Michael A.Cancer cells display oncogene-driven rewiring of metabolism to produce energy and macromolecules for growth. Inhibition of growth-promoting metabolic pathways may prove to be a useful therapeutic strategy in cancer. However, neither the full breadth of cancer cell metabolic diversity, nor the complement of mechanisms by which tumor mutations elicit metabolic reprogramming, are known. We set out to characterize cell-autonomous metabolic heterogeneity in non-small cell lung cancer (NSCLC) and to use orthogonal high-content data sets to understand the mechanisms by which metabolic phenotypes are established in lung cancer. A major goal is to understand whether these metabolic phenotypes predict therapeutic liabilities to novel metabolic inhibitors, targeted therapies, or conventional chemotherapeutic agents. We used a highly annotated panel of more than 80 NSCLC cell lines to develop the most comprehensive database of cancer cell metabolism to date. These cell lines were analyzed for a set of ~100 metabolic parameters derived from nutrient utilization, nutrient addiction, and isotope labeling patterns following culture with 13C-glucose or 13C-glutamine. Orthogonal data sets included analysis of the genome, epigenome, transcriptome and proteome, as well as sensitivity to over 40 chemotherapeutic agents. Several cell lines were also subjected to high-throughput chemical compound and genome-wide siRNA screens. NSCLC cell lines display a surprising degree of cell-autonomous metabolic heterogeneity in culture. Many canonical hallmarks of cancer cell metabolism, including the Warburg effect, were observed to span at least a 10-fold range among cell lines grown under identical conditions. Affinity propagation clustering using metabolic features alone produced families that were largely distinct from clusters based solely on gene expression. Nevertheless, databases of metabolic features and orthogonal data sets could be cross-queried to identify robust, novel relationships connecting metabolic preferences to oncogenotypes, transcriptomic phenotypes and therapeutic responses. Focused metabolic assays can produce a highly informative view of the metabolic phenotyping among large panels of cell lines. NSCLC cell metabolism is highly heterogeneous in every parameter so far assessed. Functional metabolic families describe an unparalleled view of the connections between genetics, drug sensitivity and cell-autonomous metabolism in NSCLC.Item Metastatic prostate cancer: current and emerging therapies(2014-12-05) Courtney, KevinItem Mind the gap: stepping on a bridge of life(2023-06-02) Zaha, Vlad G.