Gene Regulation and Therapeutics for Cancer

329 Pages·2021·13.752 MB·English

by  Surinder K. Batra, Moorthy Palanimuthu Ponnusamy

Gene Regulation and

Therapeutics for Cancer
Editors
Surinder K. Batra, Ph.D

and

Moorthy P. Ponnusamy, Ph.D

Department of Biochemistry and Molecular Biology

University of Nebraska Medical Center, Omaha, NE, USA

p,
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Library of Congress Cataloging-in-Publication Data
Names: Batra, Surinder K., editor. | Ponnusamy, Moorthy P., editor.
Title: Gene regulation and therapeutics for cancer / editors, Surinder K.
Batra and Moorthy P. Ponnusamy.
Description: First edition. | Boca Raton, FL : CRC Press, [2020] | Includes
bibliographical references.
Identifiers: LCCN 2020013566 | ISBN 9781138712423 (hardcover)
Subjects: MESH: Neoplasms--therapy | Molecular Targeted Therapy |
Neoplasms--genetics | Gene Expression Regulation, Neoplastic--drug
effects
Classification: LCC RC270.8 | NLM QZ 266 | DDC 616.99/406--dc23
LC record aavbaliel aabt lhe tattp hs:t/t/plcsc:/n/.llcoccn.g.loovc/.g2o0v1/62002280206113566
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Preface

Physicians and research scientists have been working “hand in hand” to find
every possible way to prevent and treat patients from the deadly disease
“cancer” since the early 1900. The fact that “cancer is a complex disease
involving several drivers and passenger mutations in multiple “oncogene
and tumor suppressor” genes makes it more challenging to identify an
appropriate drug to manage numerous signalling”. One among five thousand
pre-clinically investigated drugs will take a journey time of around 10-12
years to travel from lab bench to pharmacy shelf with 2.5 bn investment.
Hence, it is necessary to understand the root cause of its molecular mechanism
controlled by the genes and their product proteins to better manage and to
design targeted therapies.
In the first edition of this book, we focused on discussing the genes that
regulate several cancers, and available and optimized targeted therapies
along with first-line treatment options to treat such cancers. These chapters
comprehensively cover 13 different topics reviewing different cancers such
as head and neck, lung, pancreatic, prostate, breast cancers, and paediatric
Medulloblastoma. Several research scientists and physicians who are experts
in pre-clinical drug testing in mouse models and translating its benefits to
cancer centres discussed these chapters. We extensively discuss the role
of transcriptional dysregulations in cancer. The authors provide a strong
rationale to target such a transcriptional effector and the re-programming
process driving the cancer. Most targeted therapeutics developed to date
have been focused on targeting proteins encoding cell surface or cytoplasmic
kinases that function in intracellular signalling cascades while leaving a sub-
group of cell-surface proteins such as mucins. One of the chapters addresses
the regulation of mucins and targeted therapy in pancreatic cancer.
Furthermore, the authors also discuss the role and biomarker potential
of few secretory factors such as MUC5AC and exosomes in cancers. This
chapter deals with the recent development and early detection strategies
using liquid biopsies in pancreatic cancer. Because early detection is one of
the significant challenges in pancreatic cancer, it can also be used to predict
treatment response. In particular, summarized studies on the development
and contributions of PD-1-mediated immunomodulatory effects in pancreatic
cancer. One of the chapters summarizes the targeting approach of subgroup-
specific cancer epitopes for effective treatment of paediatric Medulloblastoma.
iv Gene Regulation and Therapeutics for Cancer
Furthermore, two individual chapters focus on prostate cancer biology, and
contemporary updates on clinically developed therapeutics for castration-
resistant prostate cancer were also discussed. In the final section of this
book, the applications of cancer stem cells as a promising target in cancer
therapy to abrogate aggressiveness, drug-resistance, and recurrence nature,
as observed in most solid tumors are highlighted.
We strongly believe this edition, with all the recent information, will be
very knowledgeable for students, scientists, and physicians who are working
in the field of gene regulation and targeted therapy for different cancers.
We sincerely hope that the discussed inhibitors, chemotherapy, or targeted
therapy agents will serve as a platform to design future clinical trials and aid
in curing cancer patients.
Surinder K. Batra
Moorthy P. Ponnusamy
Contents

Preface iii
1. Programmed Death 1 Receptor (PD-1)-mediated Immunomodulatory
Effects in Pancreatic Cancer 1
Ashu Shah, Catherine Orzechowski and Maneesh Jain
2. Nuclear Factor Kappa-B: Bridging Inflammation and Cancer 23
Mohammad Aslam Khan, Girijesh Kumar Patel, Haseeb Zubair,
Nikhil Tyagi, Shafquat Azim, Seema Singh, Aamir Ahmad and
Ajay Pratap Singh
3. The S100A7/8/9 Proteins: Novel Biomarker and Therapeutic
Targets for Solid Tumor Stroma 50
Sanjay Mishra, Dinesh Ahirwar, Mohd W. Nasser and
Ramesh K. Ganju
4. Nuclear Receptor Coactivators: Mechanism and Therapeutic
Targeting in Cancer 73
Andrew Cannon, Christopher Thomson, Rakesh Bhatia and Sushil Kumar
5. Liquid Biopsies for Pancreatic Cancer: A Step Towards Early
Detection 108
Joseph Carmicheal, Rahat Jahan, Koelina Ganguly, Ashu Shah and
Sukhwinder Kaur
6. Targeting Subgroup-specific Cancer Epitopes for Effective
Treatment of Pediatric Medulloblastoma 132
Sidharth Mahapatra and Naveen Kumar Perumal
7. Aberrant Methylation of UC Promoters in Human Pancreatic
Ductal Carcinomas 151
Michiyo Higashi and Seiya Yokoyama
8. Receptor Tyrosine Kinase Signaling Pathways as a Goldmine
for Targeted Therapy in Head and Neck Cancers 163
Muzafar A. Macha, Satyanarayana Rachagani, Sanjib Chaudhary,
Zafar Sayed, Dwight T. Jones and Surinder K. Batra
vi Gene Regulation and Therapeutics for Cancer
9. Molecular Drivers in Lung Adenocarcinoma: Therapeutic
Implications 185
Imayavaramban Lakshmanan and Apar Kishor Ganti
10. Molecular Mediator of Prostate Cancer Progression and
Its Implication in Therapy 207
Samikshan Dutta, Navatha Shree Sharma, Ridwan Islam
and Kaustubh Datta
11. Therapeutic Options for Prostate Cancer: A Contemporary
Update 234
Sakthivel Muniyan, Jawed A. Siddiqui and Surinder K. Batra
12. Regulation and Targeting of MUCINS in Pancreatic Cancer 264
Shailendra K. Gautam, Abhijit Aithal, Grish C. Varshney and
Parthasarathy Seshacharyulu
13. Targeted Therapy for Cancer Stem Cells 291
Rama Krishna Nimmakayala, Saswati Karmakar, Garima Kaushik,
Sanchita Rauth, Srikanth Barkeer, Saravanakumar Marimuthu and
Moorthy P. Ponnusamy
Index 321
CHAPTER
1
Programmed Death 1 Receptor (PD-1)-
mediated Immunomodulatory Effects
in Pancreatic Cancer
Ashu Shah1, Catherine Orzechowski1 and Maneesh Jain1,2*
1 Department of Biochemistry and Molecular Biology, University of Nebraska
Medical Center, Omaha, NE, USA
2 Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center,
Omaha, NE, USA
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal, treatment
refractory malignancies that has emerged as the third leading cause of cancer
related deaths in the United States. The overall five-year survival rate for
PDAC patients is dismally low at 8% with an estimated 55,440 new cases
and 44,330 deaths in the year 2018 [1]. Existing therapies for PDAC include
chemotherapy, radiotherapy, and radical surgery. However, the failure to
diagnose PDAC at an early stage makes the treatment options ineffective in
almost 80% of the patients. Even after surgery, recurrence occurs in 80% of
the patients. Till now, only five FDA approved drugs and one combination
therapy exists for PDAC patients [2]. Chemotherapy combined with
radiation has not shown much success in the patients. The reasons attributed
to inadequacy of treatment options is complex molecular landscape of
pancreatic tumors [2].
Pancreatic cancer is driven by an accumulation of several activating
mutations in the oncogene KRAS and inactivating mutations in tumor
suppressor genes TP53, CDKN2A (p16), and SMAD4 in the normal pancreatic
duct epithelium. Activating KRAS mutations are present in approximately
95% of PDAC cases and is responsible for activation of PI3K-Akt, notch
pathway, hedgehog signaling, and STAT3 pathways which are potent drivers
of tumor initiation and maintenance. In addition, shortened telomerase,
genomic instability and epigenetic alterations play significant roles in the
*Corresponding author: [email protected]
2 Gene Regulation and Therapeutics for Cancer
progression of pancreatic cancer [3]. The disease is believed to originate
from a spectrum of precursor lesions including pancreatic intraepithelial
neoplasms (PanINs), intraductal papillary neoplasm (IPMN), and mucinous
cystic neoplasm (MCN) which over several years develop into aggressive
PDAC that invades surrounding tissues and metastasize to different organs.
PDAC is characterized by dense stroma (desmoplasia) comprising
pancreatic stellate cells, fibroblasts, vascular, glial, smooth muscle cells, fat
cells, epithelial cells, and immune cells along with extracellular matrix (ECM)
and extracellular molecules surrounding epithelial cells. PDAC progression
is driven by a complex interplay between tumor cells and the surrounding
cells of stroma [4].
Immune System in Pancreatic Cancer
PDAC is characterized by infiltration of both innate and adaptive immune cells
including monocytes, macrophages (M1, M2), dendritic cells, B cells (B1, B2,
B ), T cell subtypes (T , T ), NK cells and myeloid derived suppressor cells
reg eff reg
(MDSC). Although the proportion of these immune cells may vary but their
number, location, and stage of maturation in the tumor microenvironment,
and their ultimate functional differentiation may impact tumor growth and
progression [5, 6]. Intricate cross-talk of infiltrating immune cells, with tumor
cells and other stromal cells, result in the establishment of a microenvironment
rich in immunosuppressive myeloid and lymphoid subtypes [7, 8]. PDAC is
enriched in M2 macrophages, neutrophils, CD4+ T cells, T and relatively
reg
less number of CD8+ T cells [9, 10]. Therefore, PDAC has generally been
considered as a poorly immunogenic cancer [11]. However, studies in KPC
and other pancreatic cancer mouse models have highlighted the sensitivity
of pancreatic cancer to CD8+ T cell mediated cytotoxicity [12, 13]. Also, recent
studies have clustered PDAC patients into three subtypes on the basis of
genetic and transcriptional signatures and these subtypes display differences
in their immune cytolytic activity suggesting the importance of immune
activity in PDAC [14]. Conversely, multiple studies indicate that PDAC is
characterized by lesser immune cell infiltration compared to other cancers
such as melanoma, NSCLC, and HNSC where immunotherapy has been
successful [15-17].
Checkpoint Blockade Receptor Programmed Death-1
Receptor (PD-1) in Pancreatic Cancer
Tumor cells exploit intrinsic mechanisms of immune evasion which include
reduced antigen presentation, increased expression of immunosuppressive
molecules such as PD-L1 and accumulation of antigen specific T in
regs
the tumor microenvironment resulting in immunosuppression [18]. The
immune system is characterized by its ability to distinguish between normal
cells in the body and tumor cells through the expression of costimulatory
Programmed Death 1 Receptor (PD-1)-mediated Immunomodulatory… 3
and coinhibitory molecules on immune cells called immune checkpoints.
These immune checkpoint molecules play a key role in immunoregulation
and immune homeostasis through on-off switch mechanisms and protect
the host against autoimmunity. However, tumor cells use these checkpoint
molecules to protect themselves from an attack by the immune system. One
such checkpoint protein, PD-1, is a coinhibitory receptor which is present
on conventional T cells in conjunction with other costimulatory and co-
inhibitory molecules and is an important regulator of T cell activation. PD-1
operates as off switch to limit T cell activation by interacting with its ligand,
PD-L1, present on normal cells. Under inflammatory conditions like cancer,
receptor PD-1 overexpression on T cells is congruent with upregulation of
its ligand PD-L1 on antigen presenting cells (APC) and tumor cells [19]. The
interaction between PD-1 receptor and its ligand PD-L1 leads to suppressed
T cell activation and proliferation which promotes an immunosuppressed
condition in the inflammatory microenvironment.
Extensive research over the last two decades on dense desmoplastic
stroma in PDAC has elucidated the role of the inflammatory milieu in
preventing specific and significant immune response within the tumor. Many
immunosuppressive mechanisms operate simultaneously in the PDAC
microenvironment, thus making PDAC inaccessible to immunotherapy.
Nomi et al. investigated, for the first time, the expression of PD-L1 on
human pancreatic cancer cells [20] and showed an association of PD-L1
with poor survival outcomes in PDAC patients. This was associated with
lesser number of CD8+ T cells in tumor infiltrating lymphocytes of patients
with increased PD-L1 expression. Higher PD-L1 levels in 51 human PDAC
samples have been correlated with tumor growth rather than progression
in contrast to other cancers where PD-L1 expression has been shown to be
associated with advanced stage of disease [21, 22]. However, these findings
need to be validated in studies with a larger cohort of PDAC patients. The
importance of PD-1/PD-L1 axis in pancreatic cancer was further evaluated
by testing anti-PD-L1 antibody in the Panc02 subcutaneous mouse model.
Treatment with anti-PD-L1 antibody after two weeks of tumor development
resulted in a significant reduction of tumor growth along with an increase in
tumor reactive CD8+ T cells infiltration and IFNγ, Granazyme B and perforin
secretion in the tumor. Furthermore, combination of anti-PD-L1 antibody
with the FDA approved chemotherapeutic drug Gemcitabine resulted in a
substantial decrease in tumor growth as compared to gemcitabine treatment
alone [23]. Similar results were obtained with anti-PD-L1 and anti-PD-L2
antibodies in a mouse model, with orthotopically implanted Panc02 cells
where antibody treatment resulted in significant tumor suppression along
with enhanced intratumoral infiltration of IFNγ-producing CD8+ T cells and
reduced FoxP3+ T cells [24]. However, these preclinical observations were
reg
not recapitulated in subsequent clinical studies where PDAC patients were
found to be refractory to anti-PD-1 therapy [25]. A possible explanation for
this can be the difference in heterogeneity of murine and human tumors;