Cardio-Oncology

Principles, Prevention and Management

Roberta A. Gottlieb,Puja K Mehta

• Publisher: Academic Press
• Year: 2016
• ISBN:
  9780128035535
• Topic: Medicina
• Subtopic: Cardiología

Cardio-Oncology: Principles, Prevention and Management is a clinical volume that focuses on the basic science of cardio-oncology, addresses cardiotoxicity as a consequence of cancer therapy, and discusses prevention, diagnosis and management of cardiovascular disease in patients with cancer.

This comprehensive volume presents unique perspectives ranging from basic science to clinical medicine in the field of cardio-oncology. It would be a valuable resource for cardiologists, oncologists, internists, and pediatricians caring for patients with cancer who have cardiovascular risk factors, as well as for cardio-oncology researchers.

• Covers basic science of cardio-oncology to provide readers with the necessary background
• Addresses cardiotoxicity related to current cancer therapeutic modalities
• Discusses diagnostic and management approaches of patients with underlying cardiac risk factors as well as otherwise healthy cancer patients

Chapter 1

Current Trends in Cancer Therapy

N. Sekhon

R.A. Kumbla

M. Mita Department of Hematology/Oncology Samuel Oschin Comprehensive Cancer Institute Cedars- Sinai Medical Center, Los Angeles, CA, United States

Abstract

Therapeutic agents in cancer are numerous and unique to different subtypes of malignancies. Given the different mechanisms of tumorigenesis including deleterious mutations, loss of important regulatory checkpoints, and proteins leading to uncontrolled cellular proliferation several means of targeted therapy exist. New agents in oncology including immune therapy, antiangiogenic drugs, targeted therapies, such as cyclin dependent kinase inhibitors help to target specific areas of the immune system and proliferation pathways to decrease tumor proliferation, growth, survival, and metastasis. This chapter serves to focus on the mechanisms of the new medications in cancer therapy that have changed the way we treat cancer.

Keywords

immune checkpoint blockade

angiogenesis

epidermal growth factor receptor

mammalian target of rapamycin

Her2 family

cyclin dependent kinases

PARP

PI3K/AKT pathway

Multiple studies have demonstrated that cellular development and proliferation are heavily dependent on their microenvironments and access to metabolites and growth factors. There are various signals both extracellular and intracellular that lead to a cascade of regulated events allowing for proliferation and growth. These intricate cascades are often suppressed or overexpressed in cancer biology. The goal of many novel cancer therapies is to exploit these pathways and alter signaling in order to turn off inappropriately activated kinases leading to tumorigenesis [1].

The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been studied since the 1970s since the discovery of Rapamycin (see section, mTOR Pathway). The structure of the phosphatidylinositol and the phosphorylation of different moieties of the inositol ring by the phosphatidylinositol kinase leads to production of different phosphoinositides (PIs). The PIs, such as phosphatidylinositol (4,5) bisphosphate (PIP2) are important lipid messengers that interact with PI3K affecting downstream kinases and phosphatases that regulate cellular proliferation and apoptosis [2]. Thus, alterations and mutations of these kinases can have activating consequences on the pathway, resulting in tumorigenesis, but have also been implicated in other disease, such as cardiac hypertrophy where mouse cardiac myocytes have demonstrated to grow larger in the setting of constitutive PI3K expression [3]. Studies suggested that the PI3K pathway is the most frequently altered in human tumors [4]. Given the complexity of the pathway, the authors will discuss the important aspects that have become clinically relevant. PI3K activation begins with a ligand, such as a growth factor binding to the receptor tyrosine kinase that dimerizes and activates PI3K. The activated PI3K phosphorylates PIP2 and creates phosphatidylinositol (3,4,5) trisphosphate (PIP3). The activated PIP3 then serves to activate phosatidylinositol dependent kinase (PDK1). PDK1 phosphorylates and activates protein kinase B (also known as AKT) which directly regulates many downstream transcription factors via phosphorylation, such as FOXO (a family of proapoptotic genes), IKK (family of prosurvival genes), GSK3β (controls cell cycle progression, specifically cyclin D1), mTOR (kinase involved in protein synthesis and cell proliferation), and many others [4]. AKT activation therefore regulates cellular proliferation, nutrition, and survival. The PI3K pathway has multiple checkpoints including regulation by a combined protein/lipid phosphatase known as phosphatase and tensin homolog (PTEN) located on chromosome 10. PTEN protein is known as a tumor suppressor and serves as part of the negative feedback of the PI3K pathway, specifically by dephosphorylating PIP3 [5]. The PTEN gene has been found to be mutated in its phosphatase domain and these ...