Theranostic Approach for Pancreatic Cancer

Ganji Purnachandra Nagaraju, Sarfraz Ahmad, Ganji Purnachandra Nagaraju, Sarfraz Ahmad

• Publisher: Academic Press
• Year: 2019
• ISBN:
  9780128194584
• Topic: Biological Sciences
• Subtopic: Biology
• Index: Biological Sciences

Theranostic Approach for Pancreatic Cancer modulates the biologic properties of stroma in pancreatic cancer by targeting the several chemotherapy resistance mechanisms to impede their malignant property through introducing new strategies and drugs for tackling the disease. It brings information about ongoing research as well as clinical data about pancreatic cancer and provides detailed descriptions about diagnostic and therapeutic options for easy understanding. The book discusses several topics related to pancreatic cancer, such as stem cells, drug resistance and pancreatic tumor microenvironment, the latest developments in chemotherapy for metastatic cancer and chemoprevention, and epigenome as a therapeutic strategy.

Additionally, it encompasses a discussion on theranostic clinical applications for personalized treatment and management of pancreatic cancer. The book is a valuable resource for cancer researchers, oncologists, and several members of the biomedical field who need to understand more about the diagnosis and treatment of pancreatic cancer.

• Provides information on the roadblocks of chemotherapy in patients with newly diagnosed and metastatic pancreatic cancer<
• Discusses treatment options available currently and prospective options for the future
• Focuses especially on stroma, tumor microenvironment, stem cells, stellate cells, transcription factors, growth factors, and important signaling pathways as already tested types of treatment

Chapter 1

Biology, pathophysiology, and epidemiology of pancreatic cancer

Begum Dariya¹, Afroz Alam¹, and Ganji Purnachandra Nagaraju^{2 1}Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, India ²Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States

Abstract

Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths and will become the second most prevalent one by 2030 owing to its aggressive nature. It has the worst prognosis and most limited efficiency of commonly available therapies. The incidence and mortality rate are high in developed countries. Variabilities in geography and gender are proportional to the increase in risk factors. Risk factors include an unhealthy lifestyle, and modifiable factors that cause PC are known but insufficient; therefore, a better understanding of the etiology and epidemiology of PC is essential for its prevention. Germ line mutations, hereditary disorders (familial adenomatous polyposis, familial atypical multiple mole melanoma syndrome, and hereditary nonpolyposis colorectal cancer), inherited disorders (BRCA2 mutations), and gene polymorphism are factors that control the detoxification of carcinogens from the environment and alter risk factors. Inherent resistance developed against chemotherapeutic drugs results from the occurrence of dense stroma developed, including extracellular matrix and nonneoplastic cells (fibroblasts, immune, and invasive and vascular cells), which significantly impairs the drug delivery mechanism. Hence, an increased understanding of cellular pathways including Notch, Wnt, Hedgehog, and Kristen rat sarcoma (Kras) involved in impairing DNA repair processes, cancer cell metabolism, and metastasis can provide new therapeutic strategies for developing novel therapeutic regimens. Clinically, the use of markers including diagnostic and prognostic markers and somatic altered genes such as Kras and TP53 has been investigated, although these tests remain inconsistent owing to their inappropriate clinical performance. Thus, elucidating crucial molecular mechanisms involved in the biology of PC is necessary and will enable future research aimed at developing novel and effective biomarkers for the early diagnosis and therapy of PC.

Keywords

DNA repair; Epidemiology; Kras; Notch; Pancreatic cancer; Risk factors; Wnt

List of abbreviations

APC Adenomatous polyposis coli

ARK AMPK related kinase

BRCA Breast cancer type 1

CA19-9 Carbohydrate antigen

CDCP1 CUB domain contained protein 1

CDH1 Epithelial or E-cadherin

CDKN2A Cyclin dependent kinase inhibitor 2A

DHSA Dihydrosanguinarine

DNMT DNA methyltransferase

DPC4 Deleted in PC

ECM Extracellular matrix protein

EMT Epithelial mesenchymal transition

FAMMM Familial atypical multiple mole melanoma syndrome

FOXC1 Forkhead box C1

GNAS Guanine nucleotide binding protein

GSK3β Glycogen synthase kinase 3β

HDAC Histone deacetylase

HES Hair enhance of split family

HP Hereditary pancreatitis

IGF Insulin growth factor

IPMN Intraductal papillary mucinous neoplasma

LEF Lymphoid enhancing factor

LITAF Lipopolysaccharide induced tumor necrosis-α factor

LRP5 Lipoprotein receptor related protein

MCN Mucinous cystic neoplasm

MGMT Methylguanine methyl transferase

MiRNA MicroRNA

MMP Matrix metalloproteinases

MUC Mucin

NICD Notch intracellular domain

NOX NAD(P)H oxidase

PCSC Pancreatic cancer stem cells

PDAC Pancreatic ductal adenocarcinoma

PDX Patient-derived xenografts

PSC Pancreatic stellate cells

RARβ Retinoic acid receptor β

RB Retinoblastoma

SEER Surveillance, Epidemiology and End Results

SHH Sonic Hedgehog

SIRT Sirtuin

SPARC Secreted protein acidic and rich in cysteine

TCF T-cell factor

TGF-β Transforming growth factor-β

TME Tumor microenvironment

THOR TERT hypermethylated oncologic region

UPSM Ultra–pH sensitive micelles

Introduction

Pancreatic cancer (PC) is a lethal aggressive disease with high mortality rates. It represents the fourth most frequent cause of cancer-related deaths. It will soon be ranked as the second most malignant cancer worldwide, with an overall survival rate of 26% for 1 year, 8.5% for 5 years in advanced stages of the disease, and 22% for early-stage detection with surgical resection of the tumor. Statistical analysis for PC globally estimates 1,000,000 new cases with 65,000 deaths annually [1]. According to reports from the National Cancer Institute Surveillance, Epidemiology and End Result Program, estimated new cases in 2018 were 55,440, with 44,330 deaths. The diagnosis of PC in later stages, its high inherent resistance against conventional chemotherapy, the lack of biomarkers, and insufficient treatment options result in its poor prognosis. Clinical and epidemiological studies demonstrated that early detection of neoplastic precursors and early diagnosis are effective means to regulate cancer-related mortality. Hence, the detection of pancreatic precursor lesions including mucinous cystic neoplasm (MCN), macroscopic intraductal papillary mucinous neoplasma (IPMN), and microscopic pancreatic intraepithelial neoplasia, could reduce the incidence and mortality rate of PC patients [2,3] and has been successfully tested in individuals with a strong family history of PC by imaging and surgical techniques [4–6]. PC progresses in a multistep fashion involving the transformation of healthy cells into malignant ones. This mass of malignant cells is a heterogeneous complex of tumor cells consisting of endothelial cells, immune cells, and stromal and hematopoietic cells driven by genetic alterations [7]. The most common risk factors identified include the onset of diabetes mellitus (DM), hereditary and recent pancreatitis, smoking, obesity, age, and hereditary PC, which are responsible for developing 50%–60% of PCs, whereas 5%–10% is due to genetic mutations in certain genes such as Kristen rat sarcoma (Kras). In addition to genetic mutations, epigenetic aberrations of oncogenes and silencing of tumor suppressor genes such as p16, TP53, and cyclin-dependent kinase inhibitor 2A (CDKN2A) are risk hallmarks of PC. The most common form of PC is pancreatic ductal adenocarcinoma (PDAC), which represents about 90% of PC cases. Novel therapeutic routes targeting epigenetics, modulators, and regulators of oncogenes and tumor suppressors are emerging, although molecular and pathological insights into the fatal cancer entity remain essential to improve early detection of the disease, survival time, and quality of life. This chapter highlights the epidemiology, biology, and histopathology of PC, providing an entity of tumor for therapeutic approaches to develop the survival rate and provide a better prognosis.

Epidemiology of pancreatic cancer

The asymptomatic nature of PC restricts its diagnoses to only its advanced stage with a poor prognosis. Thus, it is essential to improve methods to detect precursors at earlier stages. Furthermore, knowing and understanding the disease epidemiology could be important for primary prevention, allowing the elucidation and identification of etiology risk factors including environmental and genetical factors associated with PC. The epidemiology of PC generally measures the accurate difference of incidence and mortality rates, in which the incidence rate is the new cases and the mortality rate is the number of deaths occurring annually in a specified group. In 1999, Parkin et al. first obtained a data bank for a incidence and mortality rate from 23 areas around the world, comparing registries of cancer. They arrived at the conclusion that PC ranked ninth as the most common cause of cancer-related mortality, with 168,000 calculated deaths and the 13th cause of death in both sexes [8]. GLOBOCAN is Windows-based software that uses International Agency for Research on Cancer data to estimate the incidence and mortality rate by country. In the 2012, GLOBOCAN estimated that there were 338,000 new cases and 331,000 deaths, and thus that PC ranked seventh for mortality in both sexes [9]. It was further estimated that PC ranked 14th for new cases in 2018, with very low variations seen in males and females, but that it ranked seventh for cancer-related morality worldwide and caused 330,000 deaths per year [9]. The incidence and mortality rate are always identical because of the high fatality of disease. The incidence and mortality rates of PC calculated were higher in developed countries; they ranked second in France, fourth in the United States (North America was 7.4 per 100,000), sixth in Europe (6.8 per 100,000), and lower in countries such as Africa (2 per 100,000) and Asia (3.2 per 100,000). However, it was more commonly notic...