Targeted Therapy in Translational Cancer Research

Apostolia-Maria Tsimberidou, Razelle Kurzrock, Kenneth C. Anderson, Apostolia-Maria Tsimberidou, Razelle Kurzrock, Kenneth C. Anderson, Robert C. Bast, Jr., Maurie Markman, Ernest Hawk

• Publisher: Wiley-Blackwell
• Year: 2015
• Print ISBN: 9781118468579
• eBook ISBN: 9781118468661
• Edition: 1
• Topic: Medicine
• Subtopic: Oncology

Targeted Therapy in Translational Cancer Research for the Translational Oncology series provides a comprehensive overview of recent developments in our understanding of tumor biology, elucidates the roles of targets and pathways involved in carcinogenesis, and describes current state-of-the-art anticancer therapy, as well as the most promising areas of translational research and targeted therapy.

• Introduces cutting-edge 'bench to bedside and back' breakthroughs which have transformed the diagnosis, prognosis, and treatment of cancer
• Covers basic principles of targeted therapy, including immunotherapy and the roles of cancer stem cells, the microenvironment, angiogenesis, epigenetics, microRNAs, and functional imaging in precision medicine
• Summarises major advances in therapeutic management of hematologic malignancies and solid tumors using conventional therapy, targeted therapy, immunotherapy, or novel treatment modalities

PART I
Principles of Targeted Therapies

CHAPTER 1
Toward Personalized Therapy for Cancer

Ashley M. Holder¹ and Funda Meric-Bernstam^2,3,4

¹The University of Texas MD Anderson Cancer Center, Houston, TX, USA

²Department of Investigational Cancer Therapeutics, Houston, TX, USA

³Institute for Personalized Cancer Therapy, Houston, TX, USA

⁴Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Introduction

Personalized cancer care is grounded in the principle that the patient's genotype and molecular characterization of a tumor and its microenvironment can identify the most effective cancer management for each patient while reducing toxicity. By tailoring therapy to a specific tumor, the approach of personalized cancer therapy is expected to save critical treatment time and healthcare costs by avoiding the selection of less beneficial therapies. Thus, the objective of personalized cancer therapy is to harvest information about the tumor—its DNA, RNA, proteins, and metabolism—within the context of the tumor microenvironment and the patient's genotype to inform treatment decisions. However, much work remains to be done before this concept can be translated from the research environment to the clinical setting.

Several complementary components are necessary to achieve personalized medicine throughout the continuum of cancer care (Figure 1.1). The first phase of personalized cancer care includes risk assessment, in order to identify patients at higher cancer risk, appropriately modifying screening strategies and frequency, and offering preventive strategies. Once a cancer diagnosis is made, the care of the patient enters the second phase of personalized care—molecular characterization of the tumor to assess patient prognosis. Accordingly, patients at a high risk of recurrence can receive more intensive therapy, while patients at low risk may receive less toxic systemic therapy or may avoid additional therapy altogether.

Figure 1.1 The cancer care continuum for personalized medicine.

The third phase in personalized care involves in-depth molecular characterization of the tumor to identify potential therapeutic targets and to test for established and putative predictive markers, that is, markers predictive of response to specific therapies. Markers predictive of adverse events can be used to select regimens with the least toxicity. Early response to therapy may be monitored with pharmacodynamic markers of response.

Furthermore, as efficacy of treatment for recurrent disease improves, a growing role for biomarkers is likely to develop in monitoring early recurrence and providing a personalized program for survivorship. Although currently standardized follow-up schedules based on cancer histology and stage exist for most cancer types, more precise determination of expected prognosis (i.e., likelihood of recurrence) based on molecular subtype would personalize cancer follow-up, including the frequency of follow-up visits and the need for specialist follow-up. As many cancer treatments have long-term unintended effects, personalized survivorship programs can offer more intensive screening for patients at higher risk of developing these side effects.

Personalized Targeted Therapy

Principles of Molecular Therapeutics

Even in therapy-sensitive cancers such as breast cancer, only a subgroup of cancer patients achieve a pathologic complete response with currently available standard chemotherapy, underscoring the need to develop novel targeted therapies.^{1, 2} Therefore, an important component of personalized therapy is the delivery of individualized “targeted” therapy, directed toward molecular aberrations in specific tumors. The principle of molecular therapy is to target molecular differences between cancer cells and normal cells. To implement molecular therapeutics, targets must first be identified using genomic and proteomic techniques. Notably, numerous differences exist between cancer cells and normal cells; differentiating between cancer “drivers” that play a key role in cancer progression and survival and “passengers” that are present but not critical for cancer maintenance is a challenging but surmountable component, critical to the success of targeted therapies. Extensive preclinical studies are needed for functional characterization of the effect of specific gene alterations on cancer initiation and progression and cancer cell survival. The ideal target is usually differentially expressed or activated in cancer cells conferring cell growth and survival advantage. Thus, target inhibition induces cancer cell cytostasis or, more preferably, cancer cell death.

Predictors of Response for Patient Selection

In addition to the need for compelling therapeutic targets, drugs that inhibit the identified targets, ideally through selective inhibition, are necessary to minimize off-target toxicity. Biomarkers to detect the presence of the target within the tumor are employed to select patients who will benefit from the targeted therapy. Often, the presence of the target is pursued as a potential predictive marker; however, expression of the target itself may not be sufficient to confer sensitivity to a therapy. For example, in colorectal cancer EGFR expression assessed by immunohistochemistry (IHC) is not considered to be a reproducible marker of sensitivity to cetuximab.³ In contrast, patients with colorectal cancers bearing mutated K-ras have reproducibly been shown not to benefit from cetuximab, whereas patients with tumors bearing wild-type K-ras do benefit.^4–6 As this example demonstrates, predictive markers of response, sensitivity, and resistance must be carefully developed. Even still, most clinically approved targeted therapies have low rates of objective tumor response in single agent therapy. Furthermore, predictive markers of response and clinical benefit remain elusive. Thus, it is important that extensive preclinical modeling to identify markers of response and resistance be performed early in drug development. For targeted therapies with strong rationale for predictive markers, trials can be conducted in patients selected for or enriched for certain markers.

Pharmacodynamic Markers of Response

Early in drug development, pharmacodynamic markers of biological effect must be discovered to determine whether the putative target is inhibited by the novel therapeutic agent and to measure the extent of target inhibition and downstream signaling inhibition. Biological inhibition of the target can be assessed in surrogate tissue samples, such as skin biopsies, hair follicles, peripheral blood mononuclear cells, or platelets. However, ultimately there is value added in determining the effect of the drug on tumor cells by obtaining pre-treatment and on-treatment biopsies.

Another important goal for molecular therapeutics is the development of early biomarkers of response. The traditional approach to assessing response in clinical trials has been to treat patients for two to three cycles and then evaluate treatment response with repeat imaging. However, with the implementation of targeted therapies, the discovery of pharmacodynamic markers of response that can assess response earlier would spare patients from unnecessary toxicity, save the healthcare system the cost of administering ineffective therapy, and facilitate the transfer to alternate therapeutic regimens without further disease progression. Through assessment of biomarkers pre-treatment and o...

Table of contents

• Cover
• Translational Oncology
• Title Page
• Copyright
• List of Contributors
• Series Foreword
• Foreword
• Preface: Bench to Bedside and Back
• PART I: Principles of Targeted Therapies
• PART II: Targeted Therapy in Hematological Malignancies
• PART III: Targeted Therapy in Solid Tumors
• PART IV: Targeted Therapy for Specific Molecular Aberrations
• PART V: Future Perspectives
• Index
• EULA