Hepatocellular Carcinoma
1. What is the underlying tumor biology that is being targeted?
Systemic therapy of advanced hepatocellular carcinoma (HCC) had left behind a long record of negative phase III trials until the landmark placebo-controlled Sorafenib(Drug information on sorafenib) Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial demonstrated an impact of sorafenib on survival.[22] Advances in the imaging studies used in both the diagnosis and therapy of HCC had identified the development of the typical hypervascularity of HCC in the arterial phase, which is followed by rapid washout in the venous phase on a contrast-enhanced CT scan of the liver on a cirrhotic background. Such findings not only spurred the use of local measures against these lesions, but also gave rise to trials targeting tumor angiogenesis. The tumor itself carries frequent mutations in many tumor suppressor genes throughout its development and progression; these, coupled with the frequently compromised liver function (varying with the etiology of the liver disease), account for HCC’s notorious chemotherapy resistance. In fact, as the tumor progresses and acquires adverse prognostic features, such as vascular invasion and portal vein thrombosis, angiogenesis continues to play a critical role in metastasis and invasion. VEGF-A is one of the most potent angiogenetic factors in HCC; consequently, inhibition of VEGF-A is a key targeted therapy in HCC. In addition, basic fibroblast growth factor (bFGF) is also over expressed in HCC, and it may, along with VEGF-A, further enhance angiogenesis.[23,24] There are at least two other types of growth factor that play an important role in angiogenesis in HCC: PDGF, which stimulates formation of blood vessels, and angiopoietins, which modulate blood vessel vascularity to enhance nutrient delivery to tumor cells.[25] In addition to contributing to angiogenesis, epidermal growth factor receptor (EGFR) may also be important to the growth and metastasis of some HCCs: EGFR activation leads to activation of the downstream RAF/extracellular signal–regulated kinase (ERK) pathway and the PI3K/mTOR pathway. The mTOR pathway is a crucial part of hepatocyte malignant transformation into HCC.[26] Aberrant expression of mTOR has been demonstrated in up to 50% of HCC tissues,[27] and when mTOR becomes constitutively activated, it is associated with activation of the insulin-like growth factor (IGF) axis and upregulation of the PI3K pathway.[28] The mTOR pathway has become one of the therapeutic targets in HCC clinical trials. Raf kinase is also upregulated in HCC, representing another rational target for HCC treatment. Another possible therapeutic target—c-MET—the sole receptor of hepatocyte growth factor, is overexpressed in up to 49% of HCCs, and is associated with worse overall survival.[29]
2. How ‘targeted’ are the so-called ‘targeted drugs’?
In 2006, a new stage in HCC treatment unfolded when sorafenib improved overall survival in patients with unresectable HCC. Sorafenib is the first and only agent in the history of HCC therapy that has demonstrated an overall survival benefit; this targeted treatment—which inhibits VEGF-2, VEGF-3, PDGFR, and Raf kinases—has transformed the landscape of HCC treatment. Subsequent phase II studies using bevacizumab(Drug information on bevacizumab) and erlotinib (Tarceva; a TKI targeting EGFR) in HCC have shown promise with regard to disease stabilization and PFS. Current studies of a PI3K inhibitor and mTOR inhibitors are ongoing, making treatment of HCC the prototype for targeted therapy.
3. Is the targeted therapy also suitable for immunomodulation and/or immunoconjugation?
Similar to RCC, HCC is a tumor with potential to respond to immunomodulation, and there are case reports of spontaneous regression. Immune therapy has figured prominently in past HCC treatments: IFN was tested as a component of combination therapy for HCC (IFN, cisplatin, doxorubicin, and fluorouracil(Drug information on fluorouracil) [5-FU]), but high response rates did not confer an overall survival benefit. New studies are focusing on glypican-3, a member of the proteoglycan family that is found on the surface of HCC cells, and which is not present in nonmalignant tissue.[30] A phase I study in patients with advanced HCC used a peptide vaccine against glypican-3; the study demonstrated that patients with a cytotoxic T-cell lymphocyte frequency (percentage of both glypican-3 peptide+ and CD8+ T cells pre- and post-vaccination) of ≥ 50 had longer overall survival than those whose cytotoxic T-cell lymphocyte frequency did not reach 50.[31] There is potential interest in immunotherapy for the treatment of HCC because of the possibly lesser risk of incurring toxicities in the setting of precarious liver dysfunction.
4. In what way does the targeted therapy constitute a meaningful improvement over chemotherapy?
The key feature of targeted therapy in HCC has been the demonstration that it can offer clear survival advantages to patients undergoing treatment. With sorafenib, for the first time, patients with limited options because of known liver disease have been able to experience clinical benefit. This experience highlights the inadequacies of response rate as a reflection of benefit for patients with this disease. In fact, lack of objective tumor regression should not diminish our confidence in the efficacy of targeted therapy. By contrast, while chemotherapy drug regimens could claim higher response rates, they all failed to prolong overall survival in HCC patients.
Malignant Melanoma
1. What is the underlying tumor biology that is being targeted?
Other than the known propensity of melanoma to accelerate its growth years after a latent stage, virtually little information of much therapeutic use had been assembled in at least three decades. Two breakthroughs initiated a cascade of events leading to successful clinical applications that were covered by both The New York Times and the American Society for Clinical Oncology (ASCO) in 2010.
One powerful lead was related to a BRAF mutation. BRAF, a member of the MAP kinase signaling pathway, is involved in cell proliferation, differentiation, and apoptosis. Up to 60% of melanomas have a V600 mutation in BRAF, leaving the kinase in a constitutively active form.[32] Identification of this pathway as one that confers a growth advantage, leading to accelerated growth in the presence of additional mutations, was demonstrated in mouse models [33].
Targeted Monoclonal Antibodies With Major Impact
Another approach—trying to harness immunity against tumors—led to investigation of the importance of the cytotoxic T lymphocyte antigen-4 (CTLA-4) receptor on T cells. Antibodies to CTLA-4 prevent the negative regulation of the T-cell interactions with antigen-presenting cells. Antigen-presenting cells use CD-28 to help bind T cells while presenting peptide fregments to T cells during this positive interaction. CTLA-4 expression then becomes upregulated on the T-cell surface, and CTLA-4 binds B7 on tumor cells, which bears the antigen more tightly than CD-28 (Table 2), thereby effectively slowing the activated immune system, acting in a manner similar to that of a brake. The immunologic consequence of removing the “brake” that CTLA-4 puts on the immune system is the unleashing of T-cell–mediated immunity; this stimulation was further shown to be clinically relevant. The intense interest emanating from the unprecedented clinical successes that followed these discoveries has resulted in further inquiries into the tumor biology of melanoma and in additional developments, such as the simultaneous use of B-raf and MEK inhibitors.[34]
2. How ‘targeted’ are the so-called ‘targeted drugs’?
Until the introduction of targeted therapy with ipilimumab (Yervoy; an antibody against CTLA-4) and vemurafenib (Zelboraf, a B-raf inhibitor), the treatment of malignant melanoma in the adjuvant setting was limited to IFN—and in the metastatic setting to high-dose IL-2, radiation, and cytotoxic chemotherapy. All of these therapies, even though some were “targeted,” had minimal impact on overall survival.
Vemurafenib is an extremely potent and specific inhibitor of the BRAF V600E activating mutation, providing an effective blockade of the downstream MAP kinase pathway. This compound, introduced by Plexxikon, as well as the similarly targeted drug by GlaxoSmithKline (dabrafenib), represent a remarkably successful feat in drug development. Compared to dacarbazine(Drug information on dacarbazine), vemurafenib increased 6-month overall survival: 84% of vemurafenib-treated patients survived compared with 64% of patients treated with dacarbazine.[35] Of interest, future directions of therapy include other methods of blockading the MAP kinase pathway, such as with new inhibitors of MEK.[36] Studies are underway to investigate whether dual blockade of both B-raf and MEK can overcome acquired resistance to B-raf inhibition.
Ipilimumab does not directly target melanoma; instead, by targeting CTLA-4, it prevents application of the “brake” and allows the body’s immune system to sustain an attack on malignant cells. At the same time, it allows the immune system to attack a number of other tissues—a cause of toxic manifestations (and paradoxically an indication of “non-specific targeting”). Compared with administration of a gp100 vaccine alone, ipilimumab increased overall survival in metastatic melanoma by close to 5 months.[37] While this effect is not specifically limited to melanoma, malignant melanoma is the first tumor in which deregulating the immune system has proven effective at curbing malignant cell growth. In a similar manner, more recent data have shown that curbing the negative regulation of T cells by inhibiting PD-1 or the PD-1 ligand (PD-L1) may also improve the cytotoxic attack of T cells on a number of malignant cells, including melanoma cells.[38,39]
3. Is the targeted therapy also suitable for immunomodulation and/or immunoconjugation?
Immunomodulation has a place in the treatment of malignant melanoma, and has been proven effective with the advent of CTLA-1 and PD-1 inhibition. Ipilimumab is likely to be a prototype for the harnessing of the immune system to target malignancies. Allowing T cells to act without functional inhibition leads to improvements in overall survival in patients with melanoma.
4. In what way does the targeted therapy constitute a meaningful improvement over chemotherapy?
For a decade, cytotoxic chemotherapy had minimal benefit in the treatment of melanoma. Even the combination of chemotherapy and nonspecific immunotherapy proved futile. BRAF and MEK inhibition have shown their impressive power in halting disease progression. Vemurafenib has been proven to be more effective in the treatment of this disease than the standard cytotoxic agent, dacarbazine. Furthermore, with research in melanoma focusing squarely on targeting the MAP kinase pathway and harnessing the immune system to combat the disease, it is likely that we have seen the end of cytotoxic chemotherapy use for melanoma. In malignant melanoma, targeted therapy is the only meaningful treatment option currently available.
GIST and Other Sarcomas
We include sarcomas as a “major impact area” because even the notoriously chemo-resistant tumors that are prevalent in adults are increasingly being reclassified based on molecular profiling, leading to totally new therapeutic paradigms. GIST was the initial major success of targeted therapy—once a potent inhibitor of an activated tyrosine kinase such as imatinib(Drug information on imatinib) was identified in laboratory studies[40] and tried in a patient with advanced GIST while the drug was being tested as an inhibitor of BCR/ABL in chronic myeloid leukemia. GIST became the prototype for a notoriously chemo-resistant sarcoma that yielded to a targeted agent; the approach that led to imatinib’s success in GIST was subsequently extended to other c-kit–activating mutations. Sunitinib, sorafenib, and more recently regorafenib[41] have shown efficacy in GIST imatinib failures—regorafenib presumably by successfully targeting PDGFR-A as well as KIT, which are implicated in GIST growth and imatinib resistance.[42] In addition, other tumors of mesenchymal origin, such as dermatofibrosarcoma protuberans, have been shown to be responsive to imatinib because their growth is in part driven by PDGFR.[43] A number of sarcoma subtypes have been defined by chromosomal translocations coding for chimeric oncoproteins that promote abnormal transcription; typical translocations have been described in synovial sarcoma, epithelioid sarcoma, and Ewing sarcoma. Ewing sarcoma is associated with the rearrangement of the EWS gene, which results in IGF-1 or IGF-2 hyperactivation and susceptibility to inhibitors of the IGF pathway.[44] Alveolar soft part sarcoma’s translocation results in a fusion protein that is associated with MET autophosphorylation and activation of downstream pathways, which promote growth and angiogenesis; it has been successfully targeted by sunitinib, as well as other drugs that inhibit VEGFR-1.[45,46] The growth of giant-cell tumors is mediated by RANK-ligand (RANKL)-induced osteoclast activation; denosumab (Xgeva), an inhibitor of RANKL, is able to reverse this tumor’s locally aggressive behavior.[47] The perivascular epithelioid cell tumors (PEComas) and related lymphangioleiomyomatosis occur as part of tuberous sclerosis complex (TSC), in which mutations in TSC1 or TSC2 result in defective negative regulation of mTOR; treatment with rapalogs has been effective.[48] Trabectedin (Yondelis) is a marine product that inhibits transcription-coupled DNA repair, leading to responses in myxoid liposarcoma,[49] a tumor with a unique chromosomal rearrangement that also confers increased sensitivity to ifosfamide(Drug information on ifosfamide) and doxorubicin(Drug information on doxorubicin).[50] Pazopanib has recently been approved as a systemic treatment for the notoriously drug-resistant leiomyosarcomas.[51] Finally, paclitaxel—as well as anti-angiogenic strategies—although disappointing in many forms of sarcoma,[52] has activity against angiosarcomas.[53]
Considered in perspective, the systemic treatment of sarcomas had changed little since the landmark introductions of doxorubicin and ifosfamide for soft-tissue sarcomas and cisplatin(Drug information on cisplatin) for bone sarcomas. It is now mandatory to consider specific therapeutic targets when a tumor of mesenchymal origin requiring systemic therapy is first identified.
Financial Disclosure: Dr. Muggia has served on safety data monitoring committees for Bayer, Lilly, Pfizer, and Roche. Dr. Wu and Dr. Joseph have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentined in this article.
A 70-year-old man with a history of localized prostate cancer treated with whole-pelvis radiation therapy with a boost to the prostate, in conjunction with androgen deprivation therapy 7 years prior, presented with lower back pain. A bone scan revealed an area of activity in the sacrum. What is the most likely diagnosis?
