Targeted Therapies in Cancer (Marc Lacroix - 2014)

[marc.lacr...@gmail.com]

Targeted Therapies in Cancer
Published by Nova (https://www.novapublishers.com/catalog/product_info.php?products_id=50994&osCsid=)






BY MARC LACROIX












This book is dedicated to my family













Contents


About Marc Lacroix

Chapter 1 Innovation in the Biopharmaceutical Pipeline

Chapter 2 The Diversity of Targeted Cancer Drugs Recently Approved by the FDA

Chapter 3 Chronological List of Targeted Cancer Drugs Approved by the FDA

Chapter 4 Targeted Therapies: Detailed Description

Chapter 5 Targeted Therapy for Chronic Lymphocytic Leukemia (CLL)

Chapter 6 Targeted Therapy for HER-2-Positive Breast Cancer

Chapter 7 Targeted Therapy for Metastatic Breast Cancer - Varia

Chapter 8 Targeted Therapy for Chronic Myelogenous Leukemia (CML)

Chapter 9 Targeted Therapy for Gastrointestinal Stromal Tumors (GIST)

Chapter 10 Targeted Therapy for Metastatic Colorectal Cancer (mCRC)

Chapter 11 Targeted Therapy for Metastatic Melanoma (McM)

Chapter 12 Targeted Therapy for Multiple Myeloma (MM)

Chapter 13 Targeted Therapies for Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Chapter 14 Targeted Therapy for Metastatic Renal Cell Carcinoma (mRCC)

Chapter 15 Targeted Therapy for Gastric Cancer

Chapter 16 Targeted Therapy for Non-Small Cell Lung Cancer (NSCLC)

Chapter 17 Targeted Therapy for Myelodysplastic Syndromes (MDS)

Chapter 18 Targeted Therapy for Mantle Cell Lymphoma (MCL)













About Marc Lacroix



Born in Verviers (Wallonia, Belgium), Marc Lacroix has been working for more than 20 years in several academic institutions (University of Liège, Free University of Brussels and Jules Bordet Institute). Currently, he is director at “InTextoResearch”, an agency devoted to scientific information on cancer). He is the author of:

• “Tumor suppressor genes in breast cancer” (2008). Lacroix M. Nova Science Publishers.
• “Molecular therapy of breast cancer: classicism meets modernity” (2009). Lacroix M. Nova Science Publishers.
• “MicroRNAs in breast cancer” (2010). Lacroix M. Nova Science Publishers.
• “A concise history of breast cancer” (2011, 2013). Lacroix M. Nova Science Publishers.
• “Coding for disease: genes and cancer” (2013). Lacroix M. Nova Science Publishers.










Chapter 1


Innovation in the Biopharmaceutical Pipeline


Abstract

Developing a new medicine is a long and complex process, with risk of failure at each step. It has been estimated that the average cost to yield a single United States Food and Drug Administration (FDA)-approved drug is approximately $1.2 billion (including the cost of development failures), and the entire research and development and FDA approval process time is between 10 and 15 years. In fact, on average, from more than a million initially screened molecules only one is investigated in late stage clinical trials and is finally made available for patients.


Chapter 2


The Diversity of Targeted
Cancer Drugs Recently
Approved by the FDA


Abstract

Targeted therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. Many targeted cancer therapies, with various modes of action, have been approved by the U.S. Food and Drug Administration (FDA) since 1997; most of them are small inhibitory molecules and monoclonal antibodies interfering with signaling pathways. The field is still growing.


Chapter 3


Chronological List of Targeted Cancer Drugs Approved
by the FDA


Abstract

Here is a chronological summary of cancer targeted therapies approved by the FDA during the past 15 years. It shows the increasingly complex landscape of molecules now available to fight various types of tumors.


Chapter 4


Targeted Therapies:
Detailed Description


Abstract

Over time, tens of therapies have been approved by the FDA. They are listed in this chapter. We provide detailed data on each of these therapies.


Chapter 5


Targeted Therapy for Chronic Lymphocytic Leukemia (CLL)


Abstract

Recent advances in the treatment of CLL have moved beyond the traditional use of alkylation agents (chlorambucil and/or cyclophosphamide) and purine analogs (such as fludarabine) into regimens combining these two chemotherapy classes with FDA-approved MAbs (rituximab, alemtuzumab, ofatumumab, obinutuzumab) or Bruton TKI (ibrutinib). These agents are discussed here.


Chapter 6


Targeted Therapy for HER-2-Positive Breast Cancer


Abstract

The human epidermal growth factor receptor 2 (HER-2) is overexpressed in up to 30% of breast tumors, and before the development of HER-2-targeted therapy, HER-2 positivity was predictive of poorer clinical outcomes. With the advent of the MAb trastuzumab, the outcome of HER-2-patients has improved dramatically. Based on its substantial efficacy and good tolerability, trastuzumab has become the therapeutic gold standard for early as well as advanced breast cancer. Next to the small TKI lapatinib, which was the first approved therapy option after trastuzumab failure, several new anti-HER-2 agents are currently already available for clinical use: pertuzumab and ado-trastuzumab emtansine.


Chapter 7


Targeted Therapy for Metastatic Breast Cancer - Varia


Abstract

In MBC, besides advances in treating HER-2-positive tumors, various drugs have been recently approved by the FDA: they include ixabepilone, eribulin and everolimus.


Chapter 8


Targeted Therapy for Chronic Myelogenous Leukemia (CML)


Abstract

The development of inhibitors against Bcr-Abl has changed the landscape for the treatment of chronic myelogenous leukemia (CML) and cancer in general. Beginning with the monumental discovery and approval of imatinib for CML, a second generation of inhibitors, nilotinib and dasatinib, and more recently, bosutinib, has now gained approval for the treatment of CML. However, resistance remains a major problem, and the new inhibitor ponatinib has been developed and approved, with activity towards the common gatekeeper T315I mutation. Another drug, omacetaxine, an alkaloid derivative, was approved by the US FDA in October 2012 for the treatment of adult patients with CML with resistance and/or intolerance to two or more TKIs.


Chapter 9


Targeted Therapy for Gastrointestinal Stromal Tumors (GIST)


Abstract

Since its introduction in the field, in 2002, the TKI imatinib has become the standard of care for patients with metastatic or unresectable KIT-positive gastrointestinal stromal tumors (GIST). Imatinib functions by blocking the constitutively activated mutant KIT or PDGFR-α (gene PDGFRA), effectively shutting down the oncogenic signal that drives up to 90% of GIST. In doing so, it has transformed the management of a condition previously refractory to systemic treatments and established GIST as a model for the use of targeted therapies and oncogene addiction in solid tumors. However, while more than 80% of patients will receive clinical benefit from imatinib monotherapy, more than half will develop progressive disease by 2 years. Two other TKI, sunitinib and regorafenib, have been approved for GIST by the FDA in 2006 and 2013, respectively.



Chapter 10


Targeted Therapy for Metastatic Colorectal Cancer (mCRC)


Abstract

The use of targeted therapies has led to a substantial improvement in the OS rate of patients with mCRC. The approved MAb, bevacizumab, cetuximab and panitumumab, are part of the standard of care, yet only recently have we begun to define which patients benefit from these therapies using predictive tumor biomarkers. Other FDA-approved agents including ziv-aflibercept and regorafenib have also shown promising results.


Chapter 11


Targeted Therapy for Metastatic Melanoma (McM)


Abstract

Most non-metastatic (cutaneous) melanomas are highly curable by surgery alone. However, with poor 5-year survival, metastatic melanoma (McM) has historically been one of the most therapeutically challenging malignancies. Until recently, dacarbazine and high-dose interleukin-2 were the only agents approved by the FDA for McM. The year 2011 witnessed the approval of immunotherapy peginterferon α-2b, but also that of an anti-CTLA-4 antibody, ipilimumab, and a BRAF-targeted agent, vemurafenib, in McM, which has led to a renaissance in melanoma therapeutics. More recently approved targeted drugs are dabrafenib and trametanib. This chapter seeks to summarize the data on approved therapeutic options in McM.


Chapter 12


Targeted Therapy for Multiple Myeloma (MM)


Abstract

The outcome of patients with MM has improved significantly in the past decade with the incorporation of the immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor, bortezomib. Considering nearly all patients relapse, MM remains an active area of investigation. Several promising classes of agents, including next generation immunomodulatory agents (such as pomalidomide) and proteasome inhibitors (such as carfilzomib), have recently been approved by the FDA. This chapter provides an overview on the therapeutic agents in the treatment of MM.


Chapter 13


Targeted Therapies for Metastatic Castration-Resistant Prostate Cancer (mCRPC)


Abstract

There have been more drugs approved by the US FDA for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in the past 5 years than in the prior 3 decades. While an improvement in the understanding of the pathogenesis of CRPC has undeniably accelerated the transition of novel approaches from “bench to bedside,” the recent successes in the treatment of prostate cancer are also a result of the efforts of clinical investigators to redefine the framework in which drugs for castration-resistant disease are evaluated. This chapter will review recently approved molecules cabazitaxel, sipuleucel-T, abiraterone, denosumab, enzalutamide, and radium Ra223.


Chapter 14


Targeted Therapy for Metastatic Renal Cell Carcinoma (mRCC)


Abstract

Metastatic renal cell carcinoma (RCC) accounts for 90% to 95% of malignant neoplasms arising from the kidney. Recent advances in surgical and systemic therapies have significantly changed the management of RCC. Targeted therapies against the vascular endothelial growth factor (VEGF) (sunitinib, pazopanib, bevacizumab plus interferon alpha, sorafenib and axitinib) and the mTOR (temsirolimus, everolimus) pathways have extended the lives of the patients with advanced disease significantly, with median overall survival currently exceeding 2



Chapter 15


Targeted Therapy for Gastric Cancer


Abstract

Gastric cancer (GC) is currently the second leading cause of cancer death worldwide; unfortunately, most patients will present with locally advanced or metastatic disease. Despite recent progress in diagnosis, surgery, chemotherapy, and radiotherapy, prognosis remains poor. A better understanding of GC biology and signaling pathways is expected to improve GC therapy, and the integration of targeted therapies has recently become possible and appears to be promising. HER-2 MAb trastuzumab has led to an era of personalized therapy in GC. In addition, ramucirumab, a MAb targeting VEGFR-2, is the first biological treatment that showed survival benefits as a single-agent therapy in patients with advanced GC who progressed after first-line chemotherapy.


Chapter 16


Targeted Therapy for Non-Small Cell Lung Cancer (NSCLC)


Abstract

Most patients with lung cancer have non-small cell lung cancer (NSCLC) subtype and have advanced disease at the time of diagnosis. Improvements in both first-line and subsequent therapies are allowing longer survival for these patients. Patients with non-squamous histology may receive treatment regimens incorporating pemetrexed or bevacizumab. In patients with squamous cell carcinoma, the latter agents should be avoided because of concerns about enhanced toxicity or decreased efficacy. Second-line chemotherapy may include pemetrexed in non-squamous histology and docetaxel or an EGFR TKI (or both) in all histologist. For patients with EGFR mutation, a TKI (gefitinib, erlotinib, afatinib) may be favored for second-line therapy. Currently, only erlotinib is offered as a third-line option in unselected NSCLC patients after failure of first- and second-line chemotherapy. Maintenance therapy is emerging as a new option for patients, as are targeted therapies for particular molecular subtypes of NSCLC, such as crizotinib and the more recent ceritinib in tumors harboring the ALK gene rearrangement.
 

Chapter 17


Targeted Therapy for Myelodysplastic Syndromes (MDS)


Abstract

Myelodysplastic syndromes (MDS) are disorders of the hematopoietic stem cell in the bone marrow. While MDS were long viewed as orphan diseases without any FDA approved therapeutic options, the landscape has changed dramatically with a promise for development of exciting new therapeutics that parallels our growing understanding of the pathobiology of the disease. A series of new agents are now approved by the FDA: azacitidine, decitabine and lenalidomide.


Chapter 18


Targeted Therapy for Mantle Cell Lymphoma (MCL)


Abstract

Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma characterized by involvement of the lymph nodes, spleen, blood, and bone marrow with short remission duration to standard therapies and a median overall survival of 4-5 years. Therefore, even though MCL is one of the rarest forms of non-Hodgkin lymphoma, the need for new treatments that will lead to improvements in patient outcomes is great. Recent drugs approved by FDA include bortezomib (2006), lenalidomide (2013), and ibrutinib (2013)