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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

ABSTRACT: “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).

Renal Cell Carcinoma

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

Early observations that patients with metastatic renal cell carcinoma (RCC) who underwent nephrectomy could experience spontaneous regression of pulmonary metastasis aroused interest in immune therapy in RCC. In fact, the only US Food and Drug Administration (FDA)-approved medications before targeted therapies were all immune therapies. However, the toxicities of such treatments were often formidable, and the responses were low and unpredictable.

Preclinical studies by Kaelin et al established a relationship between mutations in von Hippel-Lindau (VHL) genes and the failure of cells to degrade hypoxia-inducible factor-1α (HIF-1α).[6] This insight into RCC biology eventually established it as the poster child for heretofore largely resistant diseases in which a targeted therapy had demonstrated success: its median overall survival of 9 months in pre−targeted drug therapy trials[7-9] has been superseded by a median overall survival time of 22 months, with rapidly evolving diverse options for targeted therapies that are refining concepts of pathway inhibition.

FIGURE 1

Angiogenic Pathways and Inhibitors Used in the Treatment of Renal Cell Carcinoma

In addition, RCC is a striking example of how knowledge of hereditary cancers has led to insight into pathways that are deranged in sporadic cancers. One common mutation in hereditary RCC (in VHL) results in an autosomal-dominant disease with a high lifetime likelihood of RCC.[10] VHL mutations also occur in up to three-quarters of sporadic RCC with clear-cell histology,[11] and accumulation of HIF-1α is a powerful activator of downstream signals involved in angiogenesis. These factors include not only VEGF, but also platelet-derived growth factor (PDGF) and the corresponding receptors (VEGFR and PDGFR). VEGF, PDGF, VEGFR, and PDGFR have all now become the therapeutic targets of tyrosine kinase inhibitors (TKIs). A second prominent pathway in RCC development was revealed in another autosomal-dominant inherited disease that frequently co-occurs with non−clear-cell RCC: tuberous sclerosis. Genetic mutations in tuberous sclerosis lead to inactivation of downstream Rheb protein, which in turn causes activation of mammalian target of rapamycin (mTOR) (Figure). mTOR plays a critical role in the development, progression, and metastatic potential of RCC, and it has also served as a successful target in the treatment of RCC, including the non−clear-cell subtype. mTOR exists in two forms: mTOR complex 1 (mTORC-1) and mTOR complex 2 (mTORC-2). mTORC-1 is the best understood form of mTOR, and it is downstream of the phosphatidylinositol-3'-kinase (PI3K)/AKT pathway. Its activation leads to activation of the p70 ribosomal protein S6 kinase (p70S6K) pathway, and activates angiogenesis through transcription of HIF-1α.[12,13]

2. How ‘targeted’ are the so-called ‘targeted drugs’?

TABLE 1

Targeted Small-Molecule Inhibitors With Major Impact

The first approved targeted therapy in RCC was sunitinib (Sutent), a multitargeted TKI that focuses mostly on the angiogenesis pathway, which encompasses VEGFR and PDGFR. In a 2005 clinical trial,[14] it demonstrated progression-free survival (PFS) and response advantages over the old standard therapy, interferon alfa (IFN-α), in treatment-naive patients with RCC. This was soon followed by the approval of a number of somewhat related agents that have different toxicity profiles and that may be active after the failure of other agents (Table 1). For example, sorafenib, a TKI that potently blocks VEGFR-2, VEGFR-3, PDGFR, and fibroblast growth factor receptor (FGFR), won approval for superior PFS, compared to placebo, in patients who had been exposed to cytokine therapies.[15] FGFR is a receptor that activates an alternate angiogenic pathway after the VEGF-related axis has been inhibited, and the fact that sorafenib targets FGFR may explain the activity of this agent in sunitinib failures. In addition, bevacizumab (Avastin; a monoclonal antibody against VEGF) and pazopanib (Votrient; a TKI that blocks all three isoforms of VEGFR [1,2, and 3]) both showed activity either in combination with IFN or as single agents in treatment-naive RCC.[16,17] In 2011, axitinib (Inlyta; a TKI targeting VEGFR-1, -2, -3, and PDGFR), another anti-angiogenic drug, showed longer PFS than sorafenib in the second-line setting.[18] In 2012, tivozanib, a TKI targeting VEGFR-1, -2, and -3, with potent activity and a long half-life, offered longer PFS than sorafenib as first-line treatment in patients with RCC,[19] again indicating the pivotal role of targeted therapy in combating angiogenesis in the treatment of RCC.

As the only first-line targeted therapy in RCC with an overall survival advantage over IFN-α, temsirolimus (Torisel), the first mTOR inhibitor to target mTORC-1, brought hope to patients with RCC, including to those with the non–clear-cell subtype.[20] Not surprisingly, everolimus (Afinitor), the first oral mTOR inhibitor that also targets mTORC-1, now is approved for patients who failed an anti-angiogentic drug, since it demonstrated a PFS advantage in the second-line setting.[21]

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

This progress based on TKIs and mTOR inhibitors should not blunt further research into immune modulation; IFN-α and interleukin-2 (IL-2) were the FDA-approved medications for RCC until the emergence of targeted therapy. The anti-angiogenic agent sunitinib has been shown to inhibit myeloid-derived stromal cells; this inhibition in turn reduces regulatory T-cell function, thus also providing immunomodulatory effects.[11] On the other hand, sorafenib inhibits the immunosuppression induced by myeloid-derived stromal cells, and can therefore potentially enhance immune function.[11] The mTOR inhibitor temsirolimus is derived from rapamycin analogs (“rapalogs”); it has been the chief component in immune modulation post organ transplantation, and it could have a significant role in immune modulation in RCC as well. Consequently, targeted therapies may also contribute to immune modulation, and their immunomodulatory effects can be utilized in the design of combination novel targeted therapies in RCC.

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

Targeted therapy has changed metastatic RCC from a disease with nearly invariable and early fatality and with extremely limited yet very toxic treatment options (such as IL-2 and IFN) into a condition that is treatable for several months to years with a variety of therapeutic agents that offer reproducible efficacy to the majority of patients, with less toxicity. Before these agents were introduced, no prior chemotherapy trial had demonstrated even a prolongation in PFS, either alone or in combination, while this endpoint has been met by all FDA-approved targeted therapies, some of which have also demonstrated overall survival advantages. Of additional importance, these achievements have led to separate RCC treatment strategies based on histology and prognostic features, and to the application of different targeted therapies in sequence. This conceptual advance—coupling treatment to the biology of RCC—represents a key direction of future cancer therapy. RCC is also leading the way in the drive to establish a rational sequential use of these therapies on the basis of biological features; IFN has been successfully displaced, and only highly selected patients now receive interleukin-2 (IL-2).

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