Future of Colorectal Cancer Therapy: Novel Targeted Pathways
San Francisco, CA—Advances in molecular profiling of colorectal cancer (CRC) are leading to an explosion in novel agents that target pathways above and beyond the epidermal growth factor receptor (EGFR). Joseph Tabernero, MD, Director of Clinical Research, Vall d’Hebron Institute of Oncology, Barcelona, discussed the future treatment of CRC at the 2011 Gastrointestinal Cancers Symposium. “The good news is there are lots of new compounds. The challenge will be to profile patients accurately, and to identify the gene signatures of those who will benefit from the individual drugs and combinations of agents,” Dr Tabernero said.
New Compounds for New Mutations
The KRAS gene has an important role in CRC because constitutive mutations of KRAS predict resistance to anti-EGFR monoclonal antibodies, including cetuximab (Erbitux) and panitumumab (Vectibix).
The role of mutations of other signal transducer proteins is now being evaluated, including BRAF, NRAS, PIK3CA, AKT, PTEN, and TP53. These also may prove to be useful “on/off” biomarkers for EGFR inhibitor efficacy in metastatic CRC, he said.
“More effective monoclonal antibodies are coming,” he reported. Promising results, including long-lasting responses, have been observed with the compounds GA201 and SYM004. “Objective response rates have been achieved in very refractory patients,” he noted.
Evolving HER-3 Target
HER-3 is also a new target, as it has been implicated as a potential mechanism of resistance to EGFR inhibitors. Anti-HER3 compounds, therefore, are in development, including MEHD7945A—a dual anti-EGFR and HER-3 monoclonal antibody—MM121, and U3-1287-AMG888.
Monoclonal Antibodies Targeting Additional Receptors
Monoclonal antibodies directed toward other receptors are the third novel concept. The insulin-like growth factor-1 receptor (IGF-1R) protein is expressed in 90% of colon cancers, whereas expression is nil in normal mucosa. Expression is associated with proliferation and tumor stage, and overexpression, seen in approximately 50% of patients, is an independent prognostic factor for worse survival.
A recent randomized phase 2 study of the IGF-1R monoclonal antibody IMC-A12 in EGFR inhibitor-refractory patients was negative, so research continues to refine the gene signature and to find an effective agent for this target.
Other potential targets are the ligand of the c-MET receptor and hepatocyte growth factor (HGF). These oncogenes are implicated in tumor invasiveness, metastasis, and proliferation; angiogenesis; and resistance to treatment. Promising efficacy was shown by an HGF inhibitor when combined with panitumumab in patients with metastatic CRC in an international randomized phase 1/2 trial, presented at the meeting by Eric Van Cutsem, MD, University Hospital Gasthuisberg, Belgium.
The study included 142 patients and evaluated the HGF inhibitor rilotumumab (AMG 102) and the IGF-1R inhibitor ganitumumab (AMG 479). The rilotumumab/panitumumab combination proved promising, with 31% responses, compared with 22% responses with panitumumab/ganitumumab, and 21% responses with panitumumab monotherapy; median progression-free survival was similar between the 2 combinations (5.2 and 5.3 months, respectively) and significantly greater than with panitumumab alone (3.7 months), Dr Van Cutsem said.
Tumor necrosis factor–related apoptosis- inducing ligand (TRAIL) and its receptors constitute another avenue. TRAIL results in colon cancer cell growth inhibition, and TRAIL-R1 expression correlates with improved disease-free survival. Conatumumab (AMG 655) is directed to TRAIL-R2 and has produced partial responses. Early-phase trials are studying this agent in combination with standard chemotherapy regimens.
Inhibiting Activation Downstream
A fourth concept is to inhibit critical downstream pathways, especially the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, which consists of protein kinases that respond to external stimuli and regulate proliferation, differentiation, and survival/apoptosis. There are at least 2 drug-related targets, RAF and MEK, in this location, for which more than a dozen inhibitors are in development.
PI3K is also dysregulated in up to 50% of patients with advanced disease, and its activation triggers a signal transduction cascade promoting cancer growth and survival. Its drug pathway includes PI3K, AKT, mTOR, TORC1-2, and PS6K. Nearly 20 relevant compounds are in development, some of which are dual inhibitors.
Potential Combinations and Challenges
Many novel agents are thought to be most effective in combination. Promising combinations are ERK pathway inhibitors (ie, an RAF inhibitor plus MEK inhibitor); PI3K pathway inhibitor combinations (ie, dual PI3K plus TORC1-2 inhibitors); ERK– and PI3K pathway inhibitor combinations (ie, PI3K plus MEK inhibitors); AKT plus MEK inhibitors; and TORC1-2 plus MEK inhibitors. These may also be combined with chemotherapy.
Despite these opportunities to stop CRC cells in their tracks, Dr Tabernero cautioned that the challenges ahead are huge. Cancer cells behave differently, depending on their molecular profile, and operate under “plastic and evolutive phenomena” that extend to both the gene level (eg, expression, mutation, amplification/deletion) and the proteomic level (activation, phosphorylation). “Cells change under the pressure of stress,” he said, “including treatment.”