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Targeted Therapy: Its Status and Promise in Selected Solid Tumors Part I

Targeted Therapy: Its Status and Promise in Selected Solid Tumors Part I

“Targeted therapy” is becoming the centerpiece of current therapeutic strategies, and is often mentioned as the desirable direction for future progress. Why and how it is replacing past approaches in the management of solid tumors is the subject of this two-part overview. Here, in Part I, we describe areas where major inroads were initially achieved by targeting angiogenesis (central to the biology of renal cell carcinoma and hepatocellular cancer) and by unraveling pathways in the heterogeneous tumors of mesenchymal origin—spurred by the identification of c-Kit–activating mutations in gastrointestinal stromal tumors (GIST) and the regressions that ensued when tumors harboring these mutations were exposed to the tyrosine kinase inhibitor imatinib (Gleevec). More recently, the successes in the treatment of the notoriously refractory malignant melanoma via the targeting of a specific BRAF mutation and via immune activation represent an unprecedented achievement of this new therapeutic direction. For each cancer discussed in the first part of our overview, as well as in Part II, which will deal with more common cancers, we briefly cover the tumor biology, how targeting was achieved, the introduction of immune modulation or immune-conjugates, and the impact these therapies are having in the disease.

Introduction

Clinical cancer therapeutics has entered an era[1] in which advances by means of targeted therapies are leading to unprecedented successes—from the impact of imatinib (Gleevec) in chronic myeloid leukemia and gastrointestinal stromal tumor (GIST) in 2004, the striking cure rates achieved with adjuvant trastuzumab (Herceptin) for human epidermal growth factor receptor 2 (HER2)-amplified breast cancer in 2005, and convincing improvements via novel agents in outcomes for hepatocellular and renal cell cancers from 2006 on—to the groundbreaking inroads into successful palliation of aggressive phases of malignant melanoma[2] and new efficacious endocrine and immunologic control of prostate cancers in the past 2 years. Personalized medicine and the need for molecular profiling have justifiably become the Holy Grail for the development of future successful weapons against cancer.[3,4]

As has often been the case, hematologic malignancies have led the way in the introduction of this new generation of therapeutics—perhaps because of easy access to tumor samples for pharmacodynamics, and the narrow spectrum of cells of origin. The situation with solid tumors is considerably more complex, and the evolution of targeted therapies for these cancers is still in its infancy. Consequently, this review (which is being presented in two parts) consists of a perspective on current opportunities and the “work in progress” and is not a compendium of clinical trials with novel targeted agents still seeking an indication. In fact, we shall focus on integrating emerging treatments with therapeutic strategies that include both the older endocrine therapies (the “original targeted therapies”) against breast and prostate cancers, and the empirically-derived successful chemotherapies, such as platinums, that are used in gynecologic cancers. At present, and for some years to come, the treatment of most solid tumors will continue to rely on a patchwork of empirically derived and newly introduced molecularly targeted agents. However, prospective identification of targets in the clinic will not only illuminate their clinical significance, but will also further accelerate drug development—witness the way in which the introduction of gefitinib (Iressa) for lung cancer was followed in less than a decade by the identification of driver mutations, new targeted drugs, and the universal adoption of molecular profiling for treatment selection. (Lung cancer will be covered in Part II).

Questions addressed

There are four fundamental questions that need to be answered about any targeted therapy.

1. What is the underlying tumor biology that is being targeted?

2. How “targeted” are the so-called “targeted drugs”?

3. Is the targeted therapy also suitable for immunomodulation and/or immunoconjugation?

4. In what way does the targeted therapy constitute a meaningful improvement over chemotherapy?

For most of the tumors we will consider, all of these questions will be covered, even though the area of immunomodulation is currently in its infancy and experimental in most instances. However, the remarkable developments in immunomodulation in a number of diseases—for example, immunotherapy in melanoma (which is covered below), and immunoconjugates in certain forms of breast cancer (covered in Part II) and in Hodgkin lymphoma represent just the beginning of a role for “targeted” immunotherapy. In fact, great excitement has been generated by the identification of new T-cell and antigen-presenting−cell stimulatory pathways targeting Programmed Death (PD)-1 or its ligand, although it is too early in the development of these pathways to assess their impact on the treatment of specific cancers.

Major impact areas

Selected solid tumor groupings best illustrate the various stages in the evolution of this targeted therapy revolution. In this review—part I of the two-part series—we consider targeted therapies for renal cell carcinoma, hepatocellular carcinoma, melanoma, and sarcomas. We have chosen to focus on these cancers because the systemic treatment of these tumors is dominated by recently introduced molecularly targeted drugs. We describe how the tumor biology in each of these cancers has been largely responsible for the therapeutic advances.

Prostate cancer (although not covered in this series) affords another example of the connection between tumor biology and the development of targeted therapies. Endocrine therapy (which targets androgen-dependent growth) has been the hallmark of the treatment of prostate cancer for several decades. During the past 2 years, refinements in targeting have led to the introduction of abiraterone (Zytiga; a steroid synthetic pathway inhibitor) and enzalutamide (Xtandi [formerly MDV3100]; an androgen receptor inactivator). Treatment of this cancer is also relying on immune-stimulation and bone-seeking radio-immunoconjugates—with all of these advances opening up new therapeutic landscapes.

While Part I highlights the way in which targeted therapies have led to unprecedented therapeutic advances in previously erratically responsive areas, Part II will deal with areas in which targeted therapies have had a major impact in special subsets of patients (eg, in breast and lung cancers), and with those areas where we expect evolving integration into treatment as molecular pathways become better understood (eg, colorectal cancer and gynecologic cancers).

Targeted therapy: how revolutionary is it?

It is important to keep in mind that some older, empirically discovered agents are actually quite targeted—eg, camptothecin derivatives that target topoisomerase I.[5] On the other hand, some “targeted therapies” that were designed to be directed against a specific target have been shown to have clinical utility for unrelated reasons (eg, sorafenib [Nexavar] was not effective as a BRAF inhibitor; its utility likely stemmed instead from effects on the vascular endothelial growth factor [VEGF] receptor [VEGFR]). Finally, recent successes in cancer treatment may yet come from empirically derived chemical entities (eg, bendamustine [Treanda], which is active against a number of hematologic malignancies).

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