PARP Inhibitors for Cancer Therapy

PARP Inhibitors for Cancer Therapy provides a comprehensive overview of the role of PARP in cancer therapy. The volume covers the history of the discovery of PARP (poly ADP ribose polymerase) and its role in DNA repair.

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Author: Nicola J. Curtin

Publisher: Humana Press

ISBN: 3319141503

Category: Medical

Page: 591

View: 660

PARP Inhibitors for Cancer Therapy provides a comprehensive overview of the role of PARP in cancer therapy. The volume covers the history of the discovery of PARP (poly ADP ribose polymerase) and its role in DNA repair. In addition, a description of discovery of the PARP family, and other DNA maintenance-associated PARPs will also be discussed. The volume also features a section on accessible chemistry behind the development of inhibitors. PARP inhibitors are a group of pharmacological inhibitors that are a particularly good target for cancer therapy. PARP plays a pivotal role in DNA repair and may contribute to the therapeutic resistance to DNA damaging agents used to treat cancer. Researchers have learned a tremendous amount about the biology of PARP and how tumour-specific defects in DNA repair can be exploited by PARPi. The “synthetic lethality” of PARPi is an exciting concept for cancer therapy and has led to a heightened activity in this area.

Targeting the DNA Damage Response for Anti Cancer Therapy

As a result of all these observations there has been a great interest in targeting the DDR to provide anti-cancer agents that may have benefit as monotherapy in cancers with high background DNA damage levels or as a means to increase the ...

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Author: John Pollard

Publisher: Springer

ISBN: 9783319758367

Category: Medical

Page: 401

View: 113

Over the past decade a complex role for DNA damage response (DDR) in tumorigenesis has emerged. A proficient DDR has been shown to be a primary cause for cellular resistance to the very many DNA damaging drugs, and IR, that are widely used as standard-of-care across multiple cancer types. It has also been shown that defects in this network, predominantly within the ATM mediated signaling pathway, are commonly observed in cancers and may be a primary event during tumorigenesis. Such defects may promote a genomically unstable environment, facilitating the persistence of mutations, any of which may provide a growth or survival advantage to the developing tumor. In addition, these somatic defects provide opportunities to exploit a reliance on remaining repair pathways for survival, a process which has been termed synthetic lethality. As a result of all these observations there has been a great interest in targeting the DDR to provide anti-cancer agents that may have benefit as monotherapy in cancers with high background DNA damage levels or as a means to increase the efficacy of DNA damaging drugs and IR. In this book we will review a series of important topics that are of great interest to a broad range of academic, industrial and clinical researchers, including the basic science of the DDR, its role in tumorigenesis and in dictating response to DNA damaging drugs and IR. Additionally, we will focus on the several proteins that have been targeted in attempts to provide drug candidates, each of which appear to have quite distinct profiles and could represent very different opportunities to provide patient benefit.

Targeting the DNA Repair Pathway in Pelvic Epithelial Cancer

"Pelvic epithelial cancer (usually referred to as ovarian cancer) represents one-fourth of the malignancies of the female genital tract.

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Author: Oreekha Amin

Publisher:

ISBN: OCLC:922582458

Category:

Page:

View: 382

" Pelvic epithelial cancer (usually referred to as ovarian cancer) represents one-fourth of the malignancies of the female genital tract. Women carrying Breast Cancer Antigen (BRCA) germline mutations are at increased risk to develop pelvic epithelial cancer, and up to 50% of all patients with pelvic epithelial cancer show functional impairment of BRCA1 [1]. These mutations in BRCA1/2 genes exhibit impaired ability to repair double-stranded DNA breaks via homologous recombination (HR). Moreover, BRCA1 mutated cancer cells were found to have over-expression of Insulin like growth factor-1 receptor (IGF-1R) levels [2, 3]. Previously, our lab reported that inhibition of IGF-1R results in growth inhibition and apoptosis of ovarian cancer cells [4]. In our current study, we assessed the correlation between IGF-1R inhibition and HR functionality of ovarian cancer cell. Interestingly, we observed the increased sensitivity of HR deficient cancer cells to IGF-1R kinase inhibitors (IGF-1Rki). Moreover, we assessed the effect of IGF-1Rki on HR DNA repair pathway and found the reduced expression of RAD51 both at protein and mRNA level. This data suggest that inhibiting the IGF-1R pathway suppresses HR. We further showed that IGF-1Rki and poly(ADP-ribose) polymerase (PARP) inhibitors act in synergy to inhibit cancer cells. This data offers a basis for future pre-clinical work involving IGF-1Rki and PARP inhibitors in patients with cancer, providing new opportunities for the development of targeted personalized cancer therapy." --

Inhibiting PARP as a Strategic Target in Cancer

Poly-ADP ribose polymerase (PARP) proteins are critical mediators of DNA repair. Many traditional anti-cancer chemotherapy agents overwhelm a cell’s ability to repair DNA damage in order to kill proliferating malignant cells.

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Author: Christina Annunziata

Publisher: Frontiers Media SA

ISBN: 9782889199556

Category:

Page:

View: 489

Poly-ADP ribose polymerase (PARP) proteins are critical mediators of DNA repair. Many traditional anti-cancer chemotherapy agents overwhelm a cell’s ability to repair DNA damage in order to kill proliferating malignant cells. Recent evidence suggests that cancers within and across tissue types have specific defects in DNA repair pathways, and that these defects may predispose for sensitivity and resistance to various classes of cytotoxic agents. Breast, ovarian and other cancers develop in the setting of inherited DNA repair deficiency, and these cancers may be more sensitive to cytotoxic agents that induce DNA strand breaks, as well as to inhibitors of PARP activity. A series of recent clinical trials has tested whether PARP inhibitors can achieve synthetic lethality in hereditary DNA repair-deficient tumors. At the current time, mutation of BRCA serves as a potential, but not comprehensive, biomarker to predict response to PARP inhibitor therapy. Mechanisms of resistance to PARP inhibitors are only recently being uncovered. Future studies seek to identify sporadic cancers that harbor genomic instability rendering susceptibility to PARP inhibitors that compound lethal DNA damage.

PARP Inhibitors for Cancer Therapy

Lastly, using triple negative breast cancer patient-derived xenografts, investigators showed that the combination of the PI3K inhibitor and PARP inhibitor significantly reduced tumor growth [204].

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Author: Nicola J. Curtin

Publisher: Humana Press

ISBN: 9783319141510

Category: Medical

Page: 591

View: 214

PARP Inhibitors for Cancer Therapy provides a comprehensive overview of the role of PARP in cancer therapy. The volume covers the history of the discovery of PARP (poly ADP ribose polymerase) and its role in DNA repair. In addition, a description of discovery of the PARP family, and other DNA maintenance-associated PARPs will also be discussed. The volume also features a section on accessible chemistry behind the development of inhibitors. PARP inhibitors are a group of pharmacological inhibitors that are a particularly good target for cancer therapy. PARP plays a pivotal role in DNA repair and may contribute to the therapeutic resistance to DNA damaging agents used to treat cancer. Researchers have learned a tremendous amount about the biology of PARP and how tumour-specific defects in DNA repair can be exploited by PARPi. The “synthetic lethality” of PARPi is an exciting concept for cancer therapy and has led to a heightened activity in this area.

DNA Repair in Cancer Therapy

This book provides a detailed discussion of combination therapies, in other words, how the inhibition of repair pathways can be coupled with chemotherapy, radiation, or DNA damaging drugs.

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Author: Mark R. Kelley

Publisher: Academic Press

ISBN: 9780128035993

Category: Medical

Page: 464

View: 959

DNA Repair and Cancer Therapy: Molecular Targets and Clinical Applications, Second Edition provides a comprehensive and timely reference that focuses on the translational and clinical use of DNA repair as a target area for the development of diagnostic biomarkers and the enhancement of cancer treatment. Experts on DNA repair proteins from all areas of cancer biology research take readers from bench research to new therapeutic approaches. This book provides a detailed discussion of combination therapies, in other words, how the inhibition of repair pathways can be coupled with chemotherapy, radiation, or DNA damaging drugs. Newer areas in this edition include the role of DNA repair in chemotherapy induced peripheral neuropathy, radiation DNA damage, Fanconi anemia cross-link repair, translesion DNA polymerases, BRCA1-BRCA2 pathway for HR and synthetic lethality, and mechanisms of resistance to clinical PARP inhibitors. Provides a comprehensive overview of the basic and translational research in DNA repair as a cancer therapeutic target Includes timely updates from the earlier edition, including Fanconi Anemia cross-link repair, translesion DNA polymerases, chemotherapy induced peripheral neuropathy, and many other new areas within DNA repair and cancer therapy Saves academic, medical, and pharma researchers time by allowing them to quickly access the very latest details on DNA repair and cancer therapy Assists researchers and research clinicians in understanding the importance of the breakthroughs that are contributing to advances in disease-specific research

Sensitization of Cancer Cells to Chemotherapy Or Olaparib by ILK Inhibition

Part I. Breast cancer, the most commonly diagnosed cancer, ranks as the second cause of cancer death among women in the United States.

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Author: Yi-Chiu Kuo

Publisher:

ISBN: OCLC:989070142

Category:

Page:

View: 729

Part I. Breast cancer, the most commonly diagnosed cancer, ranks as the second cause of cancer death among women in the United States. Chemotherapy combined with radiation and surgery has been adopted to treat breast cancer; however, the development of resistance ultimate leads to disease progression and decreases the survival rate of patients. Thus, it is of utmost importance to develop drugs to sensitize the resistant cells. T315, an integrin-linked kinase (ILK) inhibitor, has an IC50 of 1.5 μM in breast cancer cells MDA-MB-231 and MDA-MB-468. After T315 treatment or ILK knockdown, there is decrease in DNA repair proteins expression detected by western blot. Conversely, ILK overexpression increased DNA repair protein expression. Since ILK is upstream of the AKT-NF-¿B pathway, which has been shown to be associated with DNA repair, overexpression of p65 or myristoylated AKT was used to examine the DNA repair proteins as well. T315-induced ¿-H2AX foci was observed by microscopy, and DR-GFP assay demonstrated the suppression of homologous recombination caused by T315. ILK inhibition induces decrease in DNA repair proteinis through transcriptional regulation based on the results of RT-PCR, promoter reporter assay and CHIP assay. Moreover, clonogenic assay showed that ILK knockdown increased sensitivity to doxorubicin or cisplatin in MCF-7 IL-6 overexpressing cells, which has higher chemotherapeutic resistance and expression of DNA repair-related proteins than MCF-7 cells. T315 treatment or ILK knockdown also sensitized MDA-MB-231 cells to doxorubicin. In summary, the down-regulation of these proteins related with DNA repair by ILK inhibition sensitizes breast cancer cells to chemotherapeutic drugs, confirming that ILK is a target for cancer treatment to counter drug resistance. Part II. Olaparib, the first approved PARP inhibitor by US Food and Drug Administration (FDA) in 2014, shows high clinical response in ovarian cancers that harbor BRCA mutation. Olaparib is indicated as a monotherapy in ovarian cancer patients who have received three or more lines of chemotherapy and have a deleterious BRCA mutation. We then inquired whether olaparib has synergistic effects with T315 in BRCA wild-type breast cancers, since down-regulation of BRCA1 and BRCA2 by T315 is shown in part I of this dissertation. Two ovarian cancer cell lines, SKOV3 and OVCAR3 with wild-type BRCA, were used in this study. T315 showed an IC50 of 2 μM and 4 μM in SKOV3 and OVCAR3, respectively. By western-blotting, T315 or ILK knockdown decreased DNA repair proteins. In clonogenic assay, combined treatment of T315 and olaparib significantly suppressed colony formation and similar results were shown in cells with ILK knockdown combined with olaparib. Additionally, T315 treatment or ILK knockdown potentiates expression ¿-H2AX in cells simultaneously treated with olaparib. Moreover, the severity of DNA damage was measured by the comet assay. Combination of T315 and olaparib increased the mean value of tail DNA percentage compared with individual drug treatments. In short, T315 through ILK inhibition sensitized cancer cells to PARP inhibitors, which suggests cancer patients with wild-type BRCA may also benefit from PARP inhibitors when they are treated with ILK inhibitors simultaneously.

DNA Repair and Cancer

With contributions from eminent researchers, this book explores the basics and current trends in this critical field.

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Author: Srinivasan Madhusudan

Publisher: CRC Press

ISBN: 9781466577435

Category: Medical

Page: 718

View: 760

DNA repair is a rapidly advancing field in biology and these systems represent a major defense mechanism against environmental and intracellular damaging agents such as sunlight, ionizing radiation, and reactive oxygen species. With contributions from eminent researchers, this book explores the basics and current trends in this critical field. Topics include carcinogenesis as a predictive and/or prognostic biomarker for cancer therapy, nucleotide excision repair, and tumor genetics and personalized medicine. The contributions provide essential information to scientists, pharmaceutical investigators, and clinicians interested in cancer therapy.

Current Applications for Overcoming Resistance to Targeted Therapies

This book aims to provide an update on the advancements in the therapeutic arms race between cancer, clinicians and scientists alike to overcome resistance to targeted therapies.

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Author: Myron R. Szewczuk

Publisher: Springer

ISBN: 9783030214777

Category: Medical

Page: 320

View: 101

Targeted therapies were initially developed to exploit the upregulation and dependence on key oncogenic pathways critical to cancer progression. Additionally, they also presented as a method to overcome chemoresistance by supplementing conventional therapeutic regimens with targeted therapies. However, the development of resistance to these combinatorial approaches has led to the reassessment of currently available therapeutic options to overcome resistance to targeted therapy. This book aims to provide an update on the advancements in the therapeutic arms race between cancer, clinicians and scientists alike to overcome resistance to targeted therapies. Subject experts provide a comprehensive overview of the challenges and solutions to resistance to several conventional targeted therapies in addition to providing a discussion on broad topics including targeting components of the tumor microenvironment, emerging therapeutic options, and novel areas to be explored concerning nanotechnology and the epigenome.

Cancer Associated Defects in the DNA Damage Response Drivers for Malignant Transformation and Potential Therapeutic Targets

Also, rather than being a cell-intrinsic phenomenon, we increasingly appreciate that cell-cell communication is involved. The recognition and repair of DNA damage is essential to maintain normal physiology.

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Author: Marcel van Vugt

Publisher: Frontiers Media SA

ISBN: 9782889199495

Category:

Page:

View: 432

For this eBook, and the associated Research Topic in Frontiers in Genetics, entitled: ‘Cancer-associated defects in the DNA damage response: drivers for malignant transformation and potential therapeutic targets’ we have selected 10 papers that each discusses important, yet distinct aspects of the response to DNA damage in normal cells and cancer cells. Using an evolutionary conserved signaling network called the ‘DNA damage response (DDR)’ cells maintain the integrity of their genome, and thus safeguard cellular functioning and the ability to create viably progeny. Initially, the DDR appeared to consist of few linear kinase-driven pathways. However, research over the past decades in model organisms, as well as in the human system has revealed that the DDR is a complex signaling network, wired by multiple parallel pathways and displaying extensive crosstalk. Besides phosphorylation, multiple other post-translational modifications, including ubiquitination and sumoylation, are involved to achieve chromatin remodeling and initiation of DNA repair. Also, rather than being a cell-intrinsic phenomenon, we increasingly appreciate that cell-cell communication is involved. The recognition and repair of DNA damage is essential to maintain normal physiology. Multiple pathological conditions have been attributed to defective DNA repair, most notably accelerated aging, neurodegeneration and cancer. In the context of cancer, through repair of DNA damage or elimination of irreparably damaged cells, the DDR clearly has a tumor-suppressive role. Indeed, many tumor cells show partially inactivated DDR signaling, which allows proliferation in the context of DNA damage-inducing oncogenes. Simultaneously, loss of specific DDR signaling nodes creates a specific dependence of tumor cells on their remaining DDR components, and thus creates therapeutic opportunities. Especially in the context of cancer treatment, numerous targeted agents are under investigation, either to potentiate the cytotoxic effects of chemo-radiotherapy, or to induce synthetic lethality with cancer-specific alterations, with the treatment of BRCA1/2 mutant cancers with PARP1 inhibitors as a prototype example. We have selected four review articles that provide insight into the key components and the wiring of the DDR and DNA repair. Torgovnick and Schumacher review the involvement of DNA repair in the initiation and treatment of cancer, Brinkmann et al., describe the involvement of ubiquitination in DNA damage signaling and Jaiswal and Lindqvist discuss how cell-extrinsic signaling participates in communication of DNA damage to neighboring cells. In addition, Shatneyeva and colleagues review the connection between the cellular response to DNA damage and escape from immune surveillance. Concerning the therapeutic application of targeting the DDR and DNA repair, three articles were included. Krajewska and van Vugt review the wiring of homologous recombination and how this offers therapeutic opportunities. Additionally, Knittel and colleagues describe how genetic loss of the central DDR component ATM in chronic lymphocytic leukemia can be exploited therapeutically by targeting certain parallel DNA repair pathways. Syljuasen and colleagues report on how targeting of the DDR can be used as a therapeutic strategy in lung cancer. Finally, three chapters describe newly identified regulators of the cellular response to DNA damage. Von Morgen et al. describe the R2TP complex, Lezzi and Fanciluuli review the involvement of Che-1/AATF in the DDR, and Ohms and co-authors describe how retrotransposons are at the basis of increased genomic instability. Altogether, these articles describe how defective responses to DNA damage underlie disease - and especially in the context of cancer -can be exploited to better treat disease.

PI3K mTOR in Cancer and Cancer Therapy

Significant progress has been made in recent years elucidating the molecular mechanism of cancer cell proliferation, angiogenesis, and drug-resistance in relation to the PI3K-mTOR pathway and this volume provides an in-depth overview of ...

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Author: Nandini Dey

Publisher: Humana Press

ISBN: 9783319342115

Category: Medical

Page: 294

View: 412

In the post human-genome project era, cancer specific genomic maps are redesigning tumor taxonomy by evolving from histopathology to molecular pathology. The success of a cancer drug today is fundamentally based on the success in identifying target genes that control beneficial pathways. The overwhelming power of genomics and proteomics has enlightened researchers about the fact that the PI3K-mTOR pathway is the most commonly up-regulated signal transduction pathway in various cancers, either by virtue of its activation downstream of many cell surface growth factor receptors or by virtue of its collateral and compensatory circuitry with RAS-MAPK pathway. Oncogenic signaling in the majority of solid tumors is sustained via the PI3K-AKT-mTOR pathway. Because of its prominent role in many cancer types, the PI3K-mTOR pathway has become a major therapeutic target. The volume includes two complementary parts which address the problem of etiology and disease progression and is intended to portray the very basic mechanisms of the PI3K-AKT-mTOR signaling pathway’s involvement in various facets of the cancer, including stem cell renewal, cell metabolism, angiogenesis, genetic instability, and drug resistance. Significant progress has been made in recent years elucidating the molecular mechanism of cancer cell proliferation, angiogenesis, and drug-resistance in relation to the PI3K-mTOR pathway and this volume provides an in-depth overview of recent developments made in this area.​

Targeted Therapies in Breast Cancer

This is both a cause and a consequence of realizing the importance of understanding each patient's disease based not only on presenting signs and symptoms, but also, crucially, on fundamental molecular mechanisms.

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Author: Harold J. Burstein

Publisher: Oxford University Press, USA

ISBN: 9780199735679

Category: Medical

Page: 54

View: 716

The development of monoclonal antibodies and other inhibitors of specific molecules, fully utilizing the insights learned from molecular techniques such as comparative microarrays and protein expression patterns, has led to the development and FDA approval of several agents for the treatment of breast cancer, such as trastuzamab (Herceptin, targeting HER-2 positive tumors) and lapatinib (Tykerb, targeting tumors with mutated/overexpressed EGFR 1 and 2). Other agents specifically targeting the estrogen receptor, the aromatose pathway and microtubule dynamics, fulvestrant (Faslodex, targeting the ER specifically in breast cancer cells), and letrozole (Femara, targeting the aromatose pathway), raloxifene (Evista, a selective estrogen receptor modulator), ixabepilone (Ixempra, a ?-tubulin inhibitor) have also been approved for various stages and specific settings in breast cancer treatment. The current challenges in the field include further targeting of these agents as part of specific strategies for each patient (biomarker testing, pharmacogenetics, etc.), as well as follow-up and management of adverse events. Part of the Oxford American Pocket Notes series, this volume provides clinicians with the ultra-concise, evidence-based, current information and insight on implementing the latest treatment strategies, including targeted agents, into clinical practice. This portable volume is intended to provide quick, easily accessible guidance for the practicing oncologist, oncology care staff (including nurses and PAs) as well as the primary care practitioner, on the mechanism of action, dosing and administration and adverse effects of the approved targeted agents.

DNA Repair in Cancer Therapy

The book captures-for both cancer researchers and practicing oncologists dealing with hallmark "relapse" or "drug resistance" phenomena on a daily basis-the many exciting new uses of DNA repair inhibitors, either alone or in combination ...

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Author: Lawrence C. Panasci

Publisher: Springer Science & Business Media

ISBN: 9781592597352

Category: Medical

Page: 363

View: 161

A comprehensive review of the recent developments in DNA repair that have potential for translational and clinical applications. The authors explain in detail the various mechanisms by which cancer cells can circumvent anticancer therapy and limits its usefulness in patients. They also review the clinical impact of such novel inhibitors of DNA repair mechanisms as methylguanine-DNA-methyltransferase. Also examined are inhibitors of other DNA repair enzymes such as PARP and DNA-PK, now under development and close to clinical trials. The book captures-for both cancer researchers and practicing oncologists dealing with hallmark "relapse" or "drug resistance" phenomena on a daily basis-the many exciting new uses of DNA repair inhibitors, either alone or in combination with anticancer therapies.

Ovarian Cancer

With the valuable collaboration of international experts in the field, this book is intended to provide the readership with a comprehensive update in the subject of epithelial ovarian cancer.

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Author: Ivan Diaz-Padilla

Publisher: BoD – Books on Demand

ISBN: 9789535110309

Category: Medical

Page: 384

View: 826

"Ovarian Cancer: A Clinical and Translational Update" embraces the most recent advances in diagnosis and treatment of ovarian cancer. With the valuable collaboration of international experts in the field, this book is intended to provide the readership with a comprehensive update in the subject of epithelial ovarian cancer.

System Biology Analysis of the Role of DNA Repair in Cancer Treatment Outcome

In this work, a systems biology approach is used to quantitatively study the role of DNA repair pathways in determining and improving the radiation treatment outcome.

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Author: Mengdi Qian

Publisher:

ISBN: OCLC:1126570953

Category: Cancer

Page:

View: 687

Cancer is one of the most lethal and hard to cure diseases. The common treatments for cancer include surgery, radiation therapy, chemotherapy, immunotherapy and hormone therapy. Ionizing radiation (IR) is one of the main clinical treatments for cancer and it works by inducing DNA double strand breaks (DSBs), which are the most toxic DNA lesions that lead to cell death. The effectiveness of IR treatment depends on the amount of induced damage and the DNA damage repair status of the cancer cells. DSBs are repaired by multiple DNA repair pathways and this repair reduces the effectiveness of the treatment leading to resistance to IR. It has been shown in the literature that by targeting the DNA repair pathways the treatment efficacy can be modulated.In this work, a systems biology approach is used to quantitatively study the role of DNA repair pathways in determining and improving the radiation treatment outcome. Specifically, the mathematical models of DNA repair pathways, non-homologous end joining (NHEJ) and homologous recombination (HR), are developed for analyzing the role of DNA repair in enhancing the treatment sensitivity for prostate cancer (PCa) when a combination of radiation and hormone deprivation therapies is used. DSBs are repaired by one of the two DNA repair pathways: NHEJ and homologous recombination (HR). NHEJ is the major pathway, whereas HR is restricted to S- or G2-phases of the cell cycle after DNA replication has been completed. The cell cycle specific contribution of the repair pathways are incorporated into the computational models. A comprehensive identifiability analysis is carried out to determine the factors affecting parameter identifiability and strategies to increase identifiability are developed. In parallel to the NHEJ and HR models, a computational model of the base excision repair (BER) pathway is developed to analyze its role in response to chemotherapy under different treatment scenarios.Combination treatment strategies that aim to inhibit the functional DNA repair pathways for the cancer cells that are defective in other repair pathways achieve synthetic lethality. One such strategy is the use of PARP inhibitors (PARPi) in addition to the combination treatment with IR and ADT. The experimental data in the literature show that AR promotes both NHEJ and HR following IR, and inhibition of AR by ADT impairs both of these pathways in PCa cells leading to either increased radiosensitivity or sensitization to PARP inhibitors. The effect of using PARPi in this scenario has been computationally analyzed in this work by extending the modeling efforts to include the effect of PARP inhibitors on the treatment outcome. The inhibition of BER by PARPi is also quantitatively studied. The models and findings in this work can then be extended to other cancers, such as lung cancer and ovarian cancer that benefit from similar synthetic lethality.

Advances in DNA Repair in Cancer Therapy

Also examined are inhibitors of other DNA repair enzymes such as PARP and DNA-PK. The book captures-for both cancer researchers and oncologists dealing with hallmark "relapse" or "drug resistance" phenomena on a daily basis-the many ...

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Author: Lawrence Panasci

Publisher: Springer Science & Business Media

ISBN: 9781461447412

Category: Medical

Page: 312

View: 183

​A comprehensive review of the recent developments in DNA repair research that have potential for translational applications. The book explains in detail the various biological mechanisms by which cancer cells can circumvent anticancer therapy and limits its usefulness in patients. They also review the impact of such novel inhibitors of DNA repair mechanisms as methylguanine-DNA-methyltransferase. Also examined are inhibitors of other DNA repair enzymes such as PARP and DNA-PK. The book captures-for both cancer researchers and oncologists dealing with hallmark "relapse" or "drug resistance" phenomena on a daily basis-the many exciting new uses of DNA repair inhibitors, either alone or in combination with anticancer therapies.​

A Beginner s Guide to Targeted Cancer Treatments

With the help of this book, readers will be able to better understand more complex, in-depth articles in journals and books and develop their knowledge.

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Author: Elaine Vickers

Publisher: John Wiley & Sons

ISBN: 9781119126829

Category: Medical

Page: 360

View: 179

The accessible guide to the principles behind new, more targeted drug treatments for cancer Written for anyone who encounters cancer patients, cancer data or cancer terminology, but have no more than a passing knowledge of cell biology. A Beginner's Guide to Targeted Cancer Treatments provides an understanding of how cancer works and the many new treatments available. Using over 100 original illustrations, this accessible handbook covers the biology and mechanisms behind a huge range of targeted drug treatments, including many new immunotherapies. Dr Vickers translates a complex and often overwhelming topic into something digestible and easily understood. She also explains what cancer is, how it behaves and how our understanding of cancer has changed in recent years. Each chapter takes the reader through how new cancer drugs work and their benefits and limitations. With the help of this book, readers will be able to better understand more complex, in-depth articles in journals and books and develop their knowledge. This vital resource: Offers the latest insights into cancer biology Provides a broad understanding of how targeted cancer treatments work Describes many of the new immunotherapy approaches to cancer treatment, such as checkpoint inhibitors and CAR-modified T cells Helps readers feel confident discussing treatment options with colleagues and patients Provides an overview of which treatments are relevant to each of the most common solid tumours and haematological cancers, and the rationale behind them Demystifies the jargon – terms such as the EMT, cancer stem cells, monoclonal antibodies, kinase inhibitors, angiogenesis inhibitors etc. Explains the resistance mechanisms to many new treatments, including issues such as the way cancer cells diversify and evolve and the complex environment in which they live

Ovarian Cancers

This book provides an overview of the latest developments in the concepts and management of ovarian cancer. The new data presented throughout opens the way to radically different therapeutic approaches.

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Author: Eric Pujade-Lauraine

Publisher: Springer

ISBN: 9783319321103

Category: Medical

Page: 286

View: 321

This book provides an overview of the latest developments in the concepts and management of ovarian cancer. The new data presented throughout opens the way to radically different therapeutic approaches. Surgery remains the core of ovarian cancer treatment, but its ultimate goal and the standard surgical procedure have evolved, giving rise to the question of how to label expert centers for debulking surgery. Neo-adjuvant chemotherapy is becoming more popular and is also a new field for testing novel drug combinations. Over recent years, ovarian cancer management has embraced molecular biology. It is now more correct to talk about cancers of the ovary rather than ovarian cancer, since it is not a unique disease but several entities with different molecular drivers. The significant advances in drugs targeting the microenvironment or the tumor cell DNA repair mechanisms are presented in detail together with exciting future perspectives. All these advances would not have been possible without collaborative groups such as the GINECO group in France and their integration in wider clinical research networks at the European (ENGOT) and international (GCIG) level.

A Synergistic Anticancer Effect of Combination Treatment with a Cell Cycle Checkpoint Kinase 1 Inhibitor and PARP Inhibitor in BRCA Wild Type Epithelial Ovarian Cancer

Background: Theoretically, PARP inhibitors can function as a DNA damaging agents in BRCA wild type cancer, even if the clinical activity is limited.

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Author: Jae Hong No

Publisher:

ISBN: OCLC:1163852663

Category:

Page:

View: 521

Background: Theoretically, PARP inhibitors can function as a DNA damaging agents in BRCA wild type cancer, even if the clinical activity is limited. Most of epithelial ovarian cancer is characterized by TP53 mutation causing dysfunction in the G1/S checkpoint, which makes tumor cells highly dependent on Chk1-mediated G/M phase cell cycle arrest for DNA repair. Therefore, we hypothesized that combination treatment of PARP inhibitors (Rucaparib) and Chk1 inhibitor (LY2606368) would be active in BRCA wild type epithelial ovarian cancer.Methods: We investigated the anticancer effects of combination treatment with prexasertib (LY2606368) and rucaparib, in BRCA wild type ovarian cancer cell lines (OVCAR3 and SKOV3) using clinically attainable concentrations.Results: We found that combination treatment synergistically decrease cell viability in all cell lines and induces greater DNA damage and apoptosis than the control and/or monotherapies. Moreover, we identified that prexasertib can significantly inhibit homologous recombination (HR) mediated DNA repair and thus showed marked synergistic anticancer effect in combination treatment with PARP inhibitor. The synergy between prexasertib and rucaparib was considered to be caused by impaired G2/M checkpoint due to prexasertib treatment, which forced mitotic catastrophe in the presence of rucaparib. Conclusion: According to our data, prexasertib and rucaparib combination showed synergistic anticancer effects against BRCA wild type epithelial ovarian cancer cells through reduced Rad51 foci formation and greater induction of apoptosis. This might be a novel effective therapeutic strategy for BRCA-wild type epithelial ovarian cancer.