SP-050: Promising targets beyond EGFR

Abstract

HNC represent a heterogeneous disease with regard to primary site, histology, molecular signature carcinogenesis and prognosis. EGFR represent a critical target for treatment approach both in tobacco/alcohol and HPV-induced HNC. A monoclonal antibody against EGFR (Cetuximab) has gained EMA and FDA approval to treat locally advanced HNC in combination with RT and in recurrent/metastatic setting in combination with platinum based CT. However cure rate and survival remain dismal. Therefore further drugs targeting molecular pathways associated with HNC are under evaluation. The specific targeting of new pathways (such as PI3K-AKT-mTOR pathway; JAK-STAT pathway; tumor suppressive miRNAs; Notch1 and 2; epithelial to mesenchymal transformation and immunitary check points) is needed to improve survival outcomes in HNSCC. Moreover second and third generation EGFR inhibitors have the ability to overcome Cetuximab resistance for example targeting the tumor-specific EGFR deletion mutant EGFR vIII. A promising approach is also to combine several target therapy to abrogate the cross-talk between various receptor TK cascades. Phase III are currently on going using combinations of PI3K inhibitors or mTOR inhibitors and chemotherapy in platinum resistant R/M HNC (6-8% of HNCs present PIK3CA mutations). Recently studies on JAK inhibitors showed their antitumor activity in combination with EGFR inhibitors. An emerging field of treatment is to act on immune system. HNC elicits T cell anergy in both peripheral and tumor infiltrating lymphocytes (TILs) In the tumor microenviroment a low level of antimuor cytokines and co-stimulatory mediators has been reported. On the other hand co-inhibitor signals are increased (cytotoxic T lymphocyte associated antigen 4 (CTLA4) and programmed death 1 (PD-1) Successful response depends on prevalence of co-stimulator and/or block of co-inhibitory signaling on immune system A new therapeutic paradigm is to use mAb against coinhibitory receptors CTLA4 and PD1. In particular objective responses with mAbs against PDL1 correlates with PDL! expression on tumour. Moreover as in the melanoma setting the use of antiPD1 AB (BMS936559) there is also growing enthusiasm for therapeutical vaccines against HPV16-18 and p53 respectively in HPV pos and neg disease