REVIEW Advances in targeted therapies for metastatic colorectal cancer Colorectal cancer is one of the most frequently diagnosed malignancies in men and women and despite recent advances the prognosis of metastatic colorectal cancer remains poor. A better understanding of the molecular pathways that characterize tumor growth has provided novel targets in cancer therapy. Several proteins have been implicated as having a crucial role in metastatic colorectal cancer. Targets are defined according to their cellular localization, such as membrane receptor targets, intracellular signaling targets and protein kinases that regulate cell division. In the last 5 years, cetuximab, panitumumab and bevacizumab have been approved for the treatment of metastatic colorectal cancer and emerging data on the clinical development of new drugs, other than EGF-receptor and VEGF inhibitors, are likely to provide novel opportunities in the treatment of this malignancy. KEYWORDS: metastatic colorectal cancer molecular cancer biology Jose Perez-Garcia, targeted therapies Jaume Capdevila, Teresa Macarulla, Colorectal cancer (CRC) is one of the most fre- factors. One of the most important regulators Francisco Javier Ramos, quent diagnosed cancers in men and women. In of this process is VEGF and VEGFR. VEGF is Elena Elez, recent years, CRC mortality has progressively a 45-kDa homodimer that belongs to a family Manuel Ruiz-Echarri & decreased, probably owing to the availability of of growth factors comprising six different gly- Josep Tabernero† earlier diagnosis through screening, improve- coproteins: VEGF-A (commonly referred to as †Author for correspondence: ments in surgical therapies and both chemo- VEGF), -B, -C, -D, -E, and PlGF. Owing to its Medical Oncology Department, therapy and radiotherapy approaches. Better central role in tumor-associated angiogenesis, Vall d’Hebron University knowledge of the molecular cancer biology has VEGF has emerged as an attractive and central Hospital, P. Vall d’Hebron also contributed to the better outcomes of the therapeutic target in CRC. 119–129 08035, Barcelona, metastatic CRC (mCRC) population, but there Bevacizumab is a humanized anti-VEGF Spain is a need to optimize and define the best use of monoclonal antibody (mAb) that binds and neu- Tel.: +34 932 746 085 these new approaches. tralizes human VEGF [1]. In 2004, bevacizumab Fax: +34 932 746 059 Targets are defined according to their cellular was approved for first-line treatment of mCRC [email protected] localization, such as membrane receptor targets patients. Bevacizumab improved response rate (e.g., EGF-receptor [EGFR], VEGF receptor (RR), median progression-free survival (mPFS) [VEGFR], IGF-receptor [IGFR], PDGF-receptor and overall survival (OS) when given in com- [PDGFR], TNF-related apoptosis-inducing ligand bination with irinotecan-based therapy [2]. The receptor [TRAIL-R] and hepatocyte growth fac- results of the NO16966 trial that evaluated the tor receptor or C-Met), intracellular signaling addition of bevacizumab to leucovorin/5-fluo- targets (e.g., Ras/Raf/MAPK pathway, phospha- rouracil/oxaliplatin (FOLFOX) or capecitabine/ tidylinositol-3-kinase [PI3K]/AKT/mammalian oxaliplatin (XELOX) have recently been pub- target of rapamycin [mTOR] pathway, src kinase lished. The aim of the study was to demonstrate and p53/Hdm2) and protein kinases that regulate the noninferiority of XELOX versus FOLFOX cell division, such as aurora kinases (AKs) and and the superiority of bevacizumab when added polo-like kinases (Plks) (FIGURE 1). to oxaliplatin-based treatment. Bevacizumab In this review, we focus on the advances and added statistically significant improvement in development status of targeted therapies in the mPFS (8 vs 9.4 months, respectively; p = 0.0023; treatment of mCRC. hazard ratio [HR]) = 0.83) [3]. In second-line therapy, the Phase III E3200 study compared Agents targeting membrane receptors FOLFOX plus high-dose bevacizumab (10 mg/ VEGFR inhibitors kg), FOLFOX alone or bevacizumab alone and The regulation of angiogenesis is a complex, showed a statistically significant improvement in multistep process resulting from a dynamic bal- OS, mPFS and RR for the combination arm [4]. ance between proangiogenic and antiangiogenic After these results, bevacizumab was approved 10.2217/THY.09.11 © 2009 Future Medicine Ltd Therapy (2009) 6(3), 321–333 ISSN 1475-0708 321 REVIEW Perez-Garcia, Capdevila, Macarulla et al. Advances in targeted therapies for metastatic colorectal cancer REVIEW Integrins Ligands Cell (EGF, TGF-α, IGF) Growth factor receptor surface α (EGFR, IGFR, PDGFR) TRAIL-R1/R2 β uPA [P14P, P14,5, P ] [P13, 4P P13, 4, 5, P ] 2 2 2 Sos Grb2 PTEN Akt P13K K K C-src Shc C-src Ras Procaspase-8,10 NF-κβ mTOR FKHR GSK-3 Bad Raf uPAR Intracellular signaling Caspase-8,10 STAT MEK1/2 p27 Effector caspase 1 MAPK Apoptosis Cell transcription/ cell cycle progression Transcription factor Cellular responses activation Invasion Angiogenesis Survival Proliferation metastasis Figure 1. Scheme of intracellular signal transduction pathways. Ligands bind to the extracellular domain of membrane receptors, which are phosphorylated, leading to activation of several cytoplasmatic messengers, which activate transcription factors in the nucleus. The activation of transcription factors in the nucleus involves some target genes which are implicated in the proliferation, angiogenesis, apoptosis and tumor invasion processes. EGFR: EGF-receptor; FKHR: forkhead transcription factor; GRB2: growth factor receptor-bound protein 2; IGFR: IGF-receptor; mTOR: Mammalian target of rapamycin; PDGFR: PDGF-receptor; PI34P2: Phosphatidylinositol (3,4) biphosphate; PI345P3: Phosphatidylinositol (3,4,5) triphosphate; PI3K: Phosphatidylinositol 3-kinase; PTEN: Phosphatase and tensin homolog; SHC: Src homology 2 domain-containing transforming protein; SOS: Son of sevenless protein; STAT: Signal transducers and activators of transcription protein; TRAIL: TNF-related apoptosis-inducing ligand; TRAIL-R: TRAIL-receptor; uPA: Urokinase-type plasminogen activator; uPAR: Urokinase-type plasminogen activator receptor. in second-line therapy for mCRC patients. second-line chemotherapy after failing first-line The observational cohort study Bevacizumab chemotherapy in combination with bevacizumab Regimens Investigation of Treatment Effects and in patients with mCRC. Safety (BRITE) has recently been published and Hypertension is the most common beva- suggested that continuation of VEGF inhibition cizumab-related toxicity. Other toxicities of with bevacizumab beyond initial progression antiangiogenic therapy are summarized in BOX 1. could prolong OS [5]. Two ongoing prospective A variety of small-molecule tyrosine kinases randomized trials (ML18147 and Southwest (TKIs) targeting the VEGFRs are being devel- Oncology Group [SWOG] S0600) are com- oped, such as PTK-787 (vatalanib), SU-5416 paring the value of adding bevacizumab to (semaxanib), SU-11248 (sunitinib), AZD-2171 (cediranib), BAY-43–9006 (sorafenib) and Box 1. Anti-VEGF adverse effects. ZD-6474 (vandetanib). Of these, PTK-787 Hypertension is the most advanced VEGFR TKI in clinical Proteinuria development. The CONFIRM-1 study failed to Bleeding demonstrate an advantage in PFS when PTK-787 Thrombotic effects was added to FOLFOX in first-line treatment[6] . Wound healing The CONFIRM-2 study evaluated the efficacy Gastrointestinal perforation of PTK-787 in combination with FOLFOX 322 Therapy (2009) 6(3) future science group REVIEW Perez-Garcia, Capdevila, Macarulla et al. Advances in targeted therapies for metastatic colorectal cancer REVIEW versus FOLFOX alone in 855 patients with iri- bevacizumab plus chemotherapy (XELOX) with notecan-refractory mCRC. PFS was significantly or without cetuximab. Similarly, the combina- longer in the PTK-787 arm but no improvement tion of cetuximab and bevacizumab resulted in OS was demonstrated [7]. A metanalysis of the in a shorter mPFS [14]. The results of these two CONFIRM-1 and CONFIRM-2 studies showed studies suggested that there is a lack of biological that PTK-787 significantly improved PFS in synergistic effect between mAbs against EGFR patients with high lactate dehydrogenase levels (panitumumab or cetuximab) and bevacizumab [8]. Whether lactate dehydrogenase could serve in combination with chemotherapy in first-line as a surrogate marker for hypoxia and a predic- therapy of mCRC patients. A National Cancer tive factor of response to antiangiogenic therapy Institute-sponsored study (Cancer and Leukemia remains nuclear [9]. SU-11248 alone has not dem- Group B [CALGB]/SWOG 80404) comparing onstrated objective responses in refractory mCRC the addition of cetuximab, bevacizumab or both patients [10]. A randomized Phase IIb study of to standard chemotherapy – either FOLFOX or FOLFOX plus SU-11248 versus FOLFOX FOLFIRI, at the physician’s choice – in chemona- plus bevacizumab and a Phase III study of ive mCRC patients is ongoing, and should help to leucovorin/5-fluorouracil/irinotecan (FOLFIRI) define the role of these two agents used in combi- with or without SU-11248 in first-line mCRC nation in the therapeutic armamentarium. patients are currently ongoing. At the 2008 Small molecule dual inhibitors of VEGFR American Society of Oncology (ASCO) meet- and EGFR, such as vandetanib (ZD-6474) ing, a Phase II randomized study (HORIZON-1) or AEE-788, are under clinical development. of cediranib with FOLFOX versus bevacizu- A Phase II randomized study of two doses of mab with FOLFOX in patients