Optimizing treatment of metastatic colorectal cancer patients with anti-EGFR antibodies: overcoming the mechanisms of cancer cell resistance.

INTRODUCTION: A number of anti-EGFR monoclonal antibodies (mAbs) have been recently developed for the treatment of refractory metastatic colorectal cancer (mCRC). These mAbs, blocking ligand/receptor interactions, exert their biological activity via multiple mechanisms, including inhibition of cell cycle progression, potentiation of cell apoptosis, inhibition of angiogenesis, tumor cell invasion and metastasis and, potentially, induction of immunological effector mechanisms. AREAS COVERED: Cetuximab is an anti-EGFR mAb currently used in mCRC treatment. Despite the evidence of efficacy of cetuximab in the treatment of mCRC patients, the observation of low response rates was the proof of concept of resistance to anti-EGFR mAbs treatment. An increasing number of molecular alterations have been more recently hypothesized to be involved in resistance to anti-EGFR mAbs in CRC: mutations in BRAF, NRAS and PIK3CA, loss of expression of PTEN and, now, activation of HER2 signaling through HER2 gene amplification and/or increased heregulin stimulation. EXPERT OPINION: This review focuses on the development of new strategies such as combination with other agents blocking alternative escape pathways, cancer cell prioritization hyperactivating EGFR pathway, combination with immune system, development of nanotech devices to increase efficacy of antibody-based therapy and overcome the mechanisms of cancer cell resistance.

EGF-R small inhibitors and anti-EGF-R antibodies: advantages and limits of a new avenue in anticancer therapy.

Cellular receptors for the Epidermal Growth Factor (EGF-R) are members of the ErbB receptor family and are considered important targets for the experimental treatment of human cancer. Monoclonal antibodies as well as small tyrosine kinase inhibitors (TKIs) have been developed and have undergone extensive evaluation in preclinical and clinical studies based on the general idea that EGF-R plays a critical role on the growth and survival of human tumors. This assumption has been derived by the successful development of BCR/ABL tyrosine kinase inhibitors in human chronic myeloid leukemia as well as on the activity of therapy with monoclonal antibodies (mAb) in breast cancer and lymphoproliferative diseases. It is now becoming clear that factors regulating sensitivity to kinase inhibitors may differ from monoclonal antibodies and that the molecules targeted by interfering drugs must be prioritaire for growth and survival of those specific tumors in order to achieve valuable results. In this article, we will describe the signal transduction pathways regulated by EGF-R and the principal pharmacological and biotechnological agents directed against EGF-R. We will discuss the significance of targeting the EGF-R driven survival pathways and the compensatory intracellular survival mechanisms that counteract the specific EGF-R inhibition and are the cause of the poor clinical results derived from study based on the use of these agents. We will describe new multipotent TKIs that target also other members of ErbB family (i.e. ErbB2) blocking one of the compensatory mechanism that can be triggered in cancer cells. Moreover, we will report new patent on bispecific mAbs that bind EGF-R and immune effectors in order to increase the immunological function of this agent that could be the basis of the different clinical results achieved with the use of TKI and mAbs. Finally, we will propose a pharmacological model able to make cancer cells dependent on EGF-R for their survival and proliferation and we will discuss the relevance of patenting also new therapeutical strategies and not only the simple drug.

Last generation of amino-bisphosphonates (N-BPs) and cancer angio-genesis: a new role for these drugs?

Bisphosphonate (BPs) therapy has become a standard of care for patients with malignant bone disease. In addition, preclinical and preliminary clinical data suggest that BPs exert their direct or indirect antitumoral effects on cancer growth factor release, on cancer cell adhesion, invasion and viability, on cancer angiogenesis and on cancer cell apoptosis. Here, after a brief analysis on clinical indications, on the last generation amino-bisphosphonates (N-BP) and on biochemical pathways as molecular targets of BPs, we will discuss the molecular mechanisms of these antitumor effects. Recent evidence suggests that part of the antitumor activity of bisphosphonates may be attributed to an antiangiogenic effect. For this reason, we will analyse all the in vitro and in vivo preclinical reports and the first clinical evidence of anti-angiogenic activity exerted by this class of drugs. Several patents have been reported in the review, considering the recents activities observed for these drugs. Taking together all the major results obtained in the described studies, it is possible to affirm that BPs, particularly zoledronic acid and pamidronate, could potentially represent a very powerful tool for angiogenesis inhibition leading to a better control of cancer growth and progression. The translation into the clinical setting of the preclinical evidence of an antiangiogenic power of these drugs is becoming an imperative need and should represent the objective of future clinical trials.