We and others previously reported that EGFR overexpression is an early event in HNSCC carcinogenesis where EGFR represents a plausible therapeutic target [44, 49]. Targeted therapies aimed at inhibiting EGFR include monoclonal antibodies (mAb) or tyrosine kinase inhibitors. mAbs prevent ligand-binding-induced receptor activation and induce EGFR internalization. Orally available anti-EGFR TKIs block EGFR kinase activity and uncouple downstream signaling. However, in randomized placebo-controlled phase III trials, EGFR-specific TKIs have shown 195 no benefit in the treatment of HNSCC [50, 51]. Lastly, antisense DNA inhibition EGFR, via intratumoral injection is an experimental approach to abrogate EGFR signaling at the pre-translational level [52]. Although EGFR is no longer an “emerging” therapeutic target, EGFR is central to, and prototypic of, strategies aimed at inhibiting aberrantly activated pathways in HNSCC and thus is discussed below.

Currently, EGFR is the only molecular target with a US Food and Drug Administration (FDA)-approved drug, cetuximab (Erbitux®), for the treatment of primary or R/M HNSCC [53]. First approved in 2006, cetuximab is a chimeric human/murine IgG1A monoclonal antibody (mAb) with high affinity toward EGFR. Cetuximab is approved for the treatment of R/M HNSCC in combination with radiation therapy, in combination platinum-based chemotherapy, and in combination with 5-fluorouracil (5-FU) for first-line treatment of R/M HNSCC after failure of platinum-based chemotherapy and thus currently is a standard of care. Cetuximab elicits its antitumor activities via inhibition of cell proliferation, activating antibody-dependent cell-mediated cytotoxicity (ADCC), as well as potentiating the cytotoxic effects of chemotherapy and radiation therapy [54, 55].

The utility of cetuximab, despite high initial promise, has been limited. Clinical response rates to cetuximab for the treatment of R/M HNSCC are approximately 13 % and extend survival by less than 3 months [19, 55]. Strategies to select HNSCC patients who will benefit from anti-EGFR therapy remain elusive and predictive biomarkers of cetuximab response have yet to be defined. Elevated EGFR protein expression is an indicator of poor prognosis and correlates with decreased overall survival (OS) and progression-free survival (PFS) [46–48, 56]. Likewise, EGFR gene copy number, nor EGFR protein expression, has been demonstrated to be predictive of cetuximab response in HNSCC [57]. Therefore, it suggests that in a background of high EGFR expression, cetuximab concentration may be suboptimal to block all receptors, thus maintaining downstream signaling. Additional EGFR mAbs (e.g., panitumumab, zalutumumab, nimotuzumab) are currently in various phases of preclinical and clinical evaluation [58]. Results of these studies have demonstrated that other EGFR mAb confer no additional benefit in patients with R/M HNSCC over cetuximab, although select agents may yield improved adverse reaction profiles [59–61]. EGFR-specific TKIs, although promising because they are orally bioavailable, have not proven effective in unselected HNSCC populations and randomized placebo-controlled phase III clinical trials have not demonstrated a clinical benefit [50, 51].

Despite promising clinical success of these agents, the majority of patients do not respond to anti-EGFR treatment and thus demonstrate intrinsic resistance to cetuximab therapy. In those patients initially responsive to treatment, virtually all eventually exhibit secondary or acquired resistance. Thus, overcoming resistance is paramount to extend the utility of these agents and improve outcomes in HNSCC patients. Potential mechanisms of anti-EGFR resistance include overexpression and heterodimerization of other ErbB family receptors, non-ErbB family RTK activation (e.g., IGF or MET), and constitutive activation of downstream effectors (e.g., RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, and JAK/STAT3 pathways) [62–69]. Stimulation of these pathways may occur independent of EGFR pathway activation or through other stimuli such as hypoxia, induction of epithelial-mesenchymal transition (EMT), or activation of the angiogenesis pathways. Therefore, identification of biomarkers of EGFR-inhibitor response and druggable co-targets to overcome cetuximab and other EGFR-inhibitor resistance are critical.

EGFR mRNA represents a plausible target in the class of EGFR-inhibiting therapies. EGFR antisense vectors, under the control of the U6 small nuclear RNA promoter, synthesize short antisense RNA sequences which complement sense EGFR mRNA transcripts (Fig. 8.1) [49]. In one preclinical study of intratumoral injection of EGFR antisense vectors, EGFR antisense therapy inhibited tumor growth, suppressed EGFR protein expression, and induced apoptosis in HNSCC xenografts [49]. In a subsequent series of experiments, combination treatment with docetaxel in HNSCC xenografts yielded synergistic effects on proliferation and inhibition of downstream signaling through MAPK, AKT, and STAT3 signaling pathways and extended the preclinical efficacy of cytotoxic chemotherapeutics [70]. A phase I safety and biological effect study of EGFR antisense therapy was completed in 17 advanced HNSCC patients who were refractory to standard therapies [52]. In this study, a maximum tolerable dose was not achieved, no severe adverse effects were reported, and 29 % and 12 % demonstrated clinical and complete responses, respectively [52]. Currently, two phase I/II clinical trials (NCT01592721 and NCT00903461) to investigate the efficacy of AS EGFR in combination with radiation and cetuximab are ongoing [58].

One proposed mechanism of resistance to EGFR-targeted therapy is sustained pathway signaling via alternate ErbB/HER family members [65, 71]. In addition to EGFR, there are three additional ErbB/HER RTKs: HER2/neu (ErbB2), HER3 (ErbB3), and HER4 (ErbB4) (Fig. 8.1) [32]. These ErbB/HER members can form heterodimers with EGFR or with other members including HER2/HER3, HER2/HER4, and HER3/HER4. These heterodimers transduce a variety of highly regulated cellular communiqué and provide redundant and complimentary signaling that promotes tumorigenesis and EGFR resistance.

ErbB2/HER2 was originally identified as the oncogene, neu, in mouse embryonic fibroblasts [72]. Subsequently, HER2 has been demonstrated to be overexpressed or amplified in a number of human cancers, including HNSCC [73]. Activation of HER2 elicits tumor-promoting effects including proliferation, cell motility, and survival in HNSCC cells [74, 75]. HER2, unlike the other ErbB receptors, lacks a ligand-binding domain, does not have a known ligand, and requires heterodimerization with other ErbB receptors for activity [76]. Alternatively, HER2 participates non-autonomously as a signal amplifier when in a heterodimerized state. Further, heterodimerization with HER2 facilitates increased receptor recycling to the cell membrane and delays ligand dissociation from ErbB family receptors [77, 78]. Studies of association between the ErbB family members implicate HER2 as the preferred binding partner of the other ErbB family members [77, 79, 80]. The specific downstream pathways stimulated by HER2 potentiation are dependent on ligand binding and heterodimerization partners [71]. EGFR ligand binding promotes the association of EGFR/HER2 heterodimers and preferentially activates the MAPK pathway [71]. Neuregulins (e.g., NRG1, NRG2), however, stimulate HER2/HER3 heterodimerization and activate both MAPK and PI3K/AKT pathways [71]. Thus, specific prolonged ligand binding and enhanced signaling, compounded by increased recycling to the cell membrane and preferential heterodimerization, supports HER2 targeting as a for the treatment of HNSCC.

We recently reviewed the role of HER2 in the molecular biology of HNSCC [71]. Rates of overexpression range from 0 to 47 % in HNSCC; however variability in detection techniques and reporting may complicate these findings [71, 81]. HER2 has been demonstrated to be overexpressed in a subset of HNSCC [73, 82–84]. We recently reported that 4 % of The Cancer Genome Atlas (TCGA) HNSCC tumors had increased mRNA expression, of which approximately half had HER2 amplification [71, 81]. HER2 overexpression correlates with poor prognosis, recurrence, and worse OS [73, 84, 85]. HER2 expression is higher in metastatic lymph nodes than the primary tumors and is predictive of advanced disease and nodal involvement [82]. However, a recent TCGA analysis found no association between either mRNA expression or increased total or phosphorylated HER2 and OS [71]. Alternatively, HER2 expression is correlated with EGFR expression and EGFR expression is an indicator of poor prognosis [71].

Co-expression of EGFR and HER2 is associated with cetuximab resistance in preclinical HNSCC models, and thus HER2 inhibition is a logical target to extend the utility of this class of drugs [62]. Given the central importance of EGFR and EGFR-targeted therapies in the management of HNSCC, and the activation of HER2 in a subset of HNSCCs, the majority of studies investigate HER2 inhibition in the context of EGFR-therapy resistance. As with EGFR-targeted therapies, there are two main strategies to inhibit HER2: mAbs and TKIs. Trastuzumab, a mAb with high specificity to HER2, is FDA approved for the treatment of HER2-positive carcinomas of the breast. In HNSCC cells, addition of trastuzumab to gefitinib yielded a synergistic effect on proliferation in 2 of 12 cell lines [5]. The utility of lapatinib in the treatment of HNSCC, a reversible dual EGFR/HER2 TKI, was recently reviewed by Gandhi and Agulnik [86]. Laptinib inhibits HNSCC cell growth and colony formation in vitro and in vivo and enhances the efficacy of platinum-based chemotherapeutics [87]. Other multi-ErbB family TKIs with HER2 activity in preclinical and clinical development include afatinib (EGFR/HER2) and dacomitinib (EGFR/HER2/HER4) [88]. Recent investigations using these inhibitors have focused on overcoming therapy resistance. In cetuximab-defiant HNSCC clones, resistance was enhanced by activation of HER family members and MET receptors [64]. Subsequently, resistance was abrogated by gefitinib and erlotinib and the experimental pan-HER TKI canertinib [64]. We demonstrated that the EGFR/HER2 targeting TKI, afatinib, overcame cetuximab resistance in HNSCC cells in vitro and in vivo and that co-treatment yielded supra-additive effects [62]. Dacomitinib inhibited the growth of the majority of HNSCC cell lines in vitro, including cetuximab-resistant lines, and blocked EGF-stimulated MAPK and PI3K/AKT/mTOR activation to a greater extent than cetuximab [89]. Dacomitinib treatment delayed tumor growth and demonstrated additive inhibition when combined with radiation in HNSCC xenografts [90].

Clinical trials evaluating HER2-targeting drugs have yielded mixed results. In a study investigating the effect of trastuzumab on response to chemotherapy in R/M HNSCC, no clinical responses were observed [91]. Thus, trastuzumab is no longer being evaluated in the treatment of HNSCC. Lapatinib, a reversible dual EGFR/HER2 TKI with US FDA approval for co-treatment with capecitabine in HER2-overexpressing metastatic carcinomas of the breast, has been evaluated in several phase II clinical trials in HNSCC [58]. Lapatinib, when combined with chemoradiation in advanced HNSCC, was associated with higher complete response (CR), PFS, and OS rates, and this effect was most profound in p16-negative tumors [92]. In another phase II trial, lapatinib, as a single agent in R/M HNSCC, failed to demonstrate effect on survival despite suppression of pHER2 expression [21]. A larger study of previously untreated locally advanced HNSCC, lapatinib alone for 2–6 weeks, followed by cisplatin-based chemoradiation, reported equivocal results between treatments [23]. The ORR was 17 % in patients receiving lapatinib alone for at least 4 weeks; however after chemoradiation, there were no significant differences [23]. Currently there is a single open-active phase II clinical trial evaluating lapatinib in combination with carboplatin and paclitaxel as induction therapy prior to transoral surgery and risk-adapted adjuvant therapy in HNSCC (NCT01612351) [58]. Afatinib is an irreversible dual EGFR/HER2 TKI that has FDA approval for the treatment of metastatic, EGFR-mutation-positive, non-small cell lung cancer. Afatinib has demonstrated activity in phase II clinical trials in R/M HNSCC with an ORR of 16 %, which was marginally better than cetuximab in a head-to-head trial (NCT00514943) [93]. Failure in one arm allowed crossover to the other arm, which highlighted potential activity in cetuximab-resistant tumors. Currently, there are eight open-active phase II/III clinical trials evaluating afatinib in HNSCC including maintenance therapy and neoadjuvant therapy with surgery, in combination with or after failure of chemotherapy, and in postsurgical patients at high risk of recurrence [58]. Similarly, dacomitinib is an irreversible EGFR/HER2/HER4 TKI in clinical development for the treatment of R/M HNSCC [94]. A recently completed phase II study in R/M HNSCC met its primary endpoint and demonstrated a 13 % ORR with median PFS of 12.1 weeks and had favorable tolerability [94]. A second phase II clinical trial in platinum-failed R/M HNSCC demonstrated a favorable toxicity profile with a 21 % ORR and 3.9 month PFS [95]. This study identified that activating PI3K mutations and the expression of pro-inflammatory genes were negative indicators of response to dacomitinib and might serve as biomarkers of response [95]. Another pan-HER TKI, poziotinib, is in phase II clinical trials (NCT02216916) in R/M HNSCC in patients refractory to platinum; however little preclinical data are available [37, 58]. HER2 remains a promising target in the treatment of HNSCC in the context of multi-EGFR targeting drugs.

The role of HER3 in EGFR pathway signaling, HNSCC tumorigenesis, and EGFR resistance is being defined. Unlike HER2, ErbB3/HER3 maintains a ligand-binding domain but lacks catalytic activity in the kinase domain [96]. HER3 has not been shown to homodimerize but it does preferentially heterodimerize with EGFR and HER2 to potentiate their kinase activity [53]. The cognate ligand for HER3 is neuregulin (NRG1/heregulin) which preferentially induces HER2/HER3 heterodimerization and phosphorylation of tyrosine residues in the kinase domain [53, 96]. These phosphorylated residues serve as an activation site for PI3K, a downstream target of EGFR pathway activation and potent oncogenic signaling mediator (Fig. 8.1) [53]. HER2/HER3 heterodimers elicit strong activation of the PI3K/AKT survival pathway emphasizing the importance of the HER3-PI3K pathway node in tumorigenesis [65]. It is proposed that HNSCC tumors require PI3K signaling to maintain a pro-survival phenotype [19, 55]. Therefore, blocking HER3 may inhibit pro-survival signaling via PI3K. However, because HER3 has intrinsically low levels of tyrosine kinase activity, the development of small molecule inhibitors has lagged.

Few studies have reported the prognostic significance of HER3 expression in HNSCC. Takikita et al. reported that membranous HER3 expression is associated with poor prognosis and decreased survival and was more predictive of decreased survival than HER2 expression [97]. In a study of 750 tumors, of which 127 were from the head and neck, expression of the HER3 cognate ligand NRG1 was highest in HNSCC in the absence of gene amplification. HER3 expression correlated with HER3 activation and was higher in metastatic lymph nodes [88, 98]. Oncogenic activation of HER3 is independent of activating genetic events such as amplification or mutation in HNSCC [88, 98]. Alternatively, oncogenic HER3 activation is driven in a NRG1-mediated autocrine feedback loop [98]. Thus it is likely that HER3 represents a driver of tumorigenesis and resistance to EGFR-targeted therapies in HNSCC and, like HER2, may be a candidate for molecular targeted therapies.

There are few preclinical studies investigating HER3-targeted therapies in HNSCC. The efficacy of HER3 mAb MM-121 was demonstrated in HNSCC models in vitro and in vivo, and additive effects were demonstrated when combined with cetuximab [99]. MEHD7945A, a dual-targeted mAb against EGFR and HER3, reported superior anticancer effects in HNSCC cells and xenografts and overcome acquired resistance to cetuximab or erlotinib treatment [66]. Furthermore, treatment with MEHD7945A overcame cross-resistance to radiation with enhanced DNA damage and abrogated pro-survival and DNA repair pathway signaling [66]. Currently, MEHD7945A is the only HER3-targeted therapy phase II for HNSCC (NCT01577173) [52, 58]. This open-label phase II clinical trial is comparing cetuximab therapy to MEHD7945A in patients who have progressed on platinum-based chemotherapies [58].

SRC is a cytoplasmic protein belonging to the Src-family of non-receptor tyrosine kinases (SFKs) including: YES, FYN, LYN, LCK, HCK, FGR, BLK, and YRK [57]. SRC integrates signal transduction from a range of stimuli including growth factors, integrins, and G protein-coupled receptors (Fig. 8.1) [100]. Aberrant SRC activation is implicated in tumorigenesis by stimulating proliferation, cell migration, invasion, epithelial-mesenchymal transition, angiogenesis, and metastasis [101, 102]. SRC is frequently activated in epithelial malignancies including HNSCC [100, 103]. In normal epithelium SRC expression is low and expression is progressively increased in inflamed, hyperplastic, and dysplastic oral epithelium and with advancement to squamous cell carcinoma [104]. In a Taiwanese cohort, high SRC protein expression was significantly associated with progression, recurrence, and poor prognosis [105]. Furthermore, aggressive clinical features (e.g., invasive phenotype, poor differentiation, and lymph node metastasis) correlate with activation of SRC in HNSCC [102]. In total, SFKs are activated (overexpressed) in up to 29 % of HNSCC with SRC specifically activated in 14 % of cases [106]. In addition, sustained SRC activation, through alternate receptor signaling pathways, provides an avenue of resistance to current RTK-targeted therapies [69, 107]. We reported that SRC is activated downstream of EGFR in HNSCC [108]. SRC activation mediates resistance to EGFR-targeted therapies such as cetuximab and TKIs, erlotinib, and gefitinib [63, 69, 109, 110]. Thus SRC represents a “node of convergence” and positions it as a promising target for therapeutic intervention [101, 107].

Preclinical evidence supports the continued investigation of SRC TKIs in the treatment of HNSCC. We demonstrated that SRC directly interacts with EGFR upon ligand binding, stimulating invasion, and proliferation of HNSCC cells, whereas SRC inhibition blocked EGFR-mediated proliferation and invasion [108, 111]. Likewise, saracatinib, a SFK-selective TKI, disrupts the invasive phenotype of HNSCC cells [112]. We found that saracatinib, when combined with gefitinib, abrogated gefitinib resistance with enhanced anti-tumor effects in HNSCC cells [110]. Dasatinib, an FDA-approved orally available multi-TKI, inhibited the proliferation, invasion, and cell migration and induced cell cycle arrest and apoptosis in HNSCC cells at clinically relevant concentrations [100]. We reported that combination treatment with erlotinib and dasatinib overcame ligand-independent (MET-mediated) erlotinib resistance and improved HNSCC inhibition in vitro and in vivo [69, 109]. It has also been shown that cetuximab resistance is mediated by SRC activation in HNSCC cells and that low-dose dasatinib could sensitize resistant cells [63]. Furthermore, dasatinib prevents radiation- and cetuximab-induced EGFR nuclear translocation and thus prevents EGFR-mediated DNA damage repair in vitro and in vivo [113–115]. In addition to MET, the insulin-like growth factor receptor (IGF1R) pathway is another RTK-activated pathway mediating EGFR-targeted therapy resistance [107]. Coadministration of dasatinib and an IGF1R TKI or mAb resulted in synergistic anticancer responses [107, 116]; and combined SRC and JAK2 inhibition resulted in a synergistic anti-tumor effect in patient-derived xenografts [117]. In summary, preclinical evidence suggests that SRC behaves like a hub for routing oncogenic signaling and resistance to pathway-targeted therapies.

Two SRC-targeting TKIs have been investigated in single-agent phase II clinical trials, saracatinib and dasatinib. Fury et al. evaluated saracatinib, a nonselective SFK TKI, in 9 patients with R/M HNSCC; however, the study was terminated early due to lack of activity (all patients had progressive disease) [118]. Because of its safety profile and poor clinical performance, the manufacturer of saracatinib is no longer supporting any continued clinical investigations [119]. Brooks et al. (2010) completed a phase II clinical trial investigating the efficacy of single-agent dasatinib, an orally available multi-TKI (i.e., BCR/ABL, SRC, c-KIT, ephrin receptors), in platinum-refractory R/M HNSCC and measured relevant cytokines and angiogenic factors [120]. This study failed to demonstrate significant activity as 12 of 15 patients evaluable for clinical responses demonstrated no ORs and only two (16 %) had stable disease (SD) despite a rapid and complete inhibition of SRC protein [120]. Based on the preclinical evidence, and the lack of efficacy of single-agent therapy, it is likely that the clinical utility of SRC may be in combination with targeted therapies such as cetuximab. Currently, only dasatinib is being investigated in two ongoing clinical trials in the treatment of HNSCC. The first is a phase I/II randomized clinical trial investigating dasatinib, cetuximab, and radiation, with or without cisplatin in locally advanced HNSCC (NCT00882583) [58]. The second is an open-label, single-arm phase II trial of cetuximab and dasatinib in cetuximab-resistant R/M HNSCC [58].

High-throughput sequencing of HNSCC tumors has elucidated a complex array of altered signaling pathways that converge on four distinct cellular processes: mitogenic signaling, differentiation, cell cycle, and apoptosis [121–123]. Mutated, aberrantly activated, and/or amplified genes within these pathways provide rational druggable targets for intervention. One of the major contributors to tumorigenesis in HNSCC is the activation of mitogenic signaling through the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway [123]. PI3K/AKT/mTOR signaling controls critical cellular functions including survival, growth, and development and differentiation (Fig. 8.1) [71, 124]. Activation of EGFR family dimerization following ligand binding recruits PI3K family kinases to the membrane leading to the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP₂) and its conversion to the second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP₃) [125]. PIP₃ then serves as a membrane docking site for the serine/threonine protein kinase AKT (protein kinase B/PKB) [77, 78, 125]. AKT is then phosphorylated/activated by phosphoinositide-dependent kinase 1 (PDK1) and mTOR complex 2 (mTORC2). Conversely, PTEN negatively controls the activation of AKT by recycling PIP₃ to PIP_2. Activation of AKT has multiple downstream targets controlling cell survival, proliferation, angiogenesis, metabolism, and migration. A major downstream effector of pAKT is mTOR and the catalytic subunit mTOR complex 1 (mTORC1) [77, 79, 80, 125]. The kinase function of mTOR has two well-known substrates, S6 kinase 1 and 4E-BP1. Activation of S6K1 initiates protein synthesis whereas 4E-BP1 cancels the initiation of translation, thus antagonizing its action. Therefore, the major role of mTOR is the growth factor- and nutrient availability-dependent control of protein translation and likely the main mechanism of the anticancer effects elicited by rapamycin [71, 125]. Emerging druggable targets of this pathway include PIK3CA, AKT, and mTOR, and inhibitors are currently being evaluated in preclinical and clinical trials.

Proliferation of eukaryotic cells involves the well-controlled progression through four phases of the cell cycle: G₁, S, G₂, and M [210]. At the center of cell cycle regulation are cyclins (CDCs) and cyclin-dependent kinases (CDKs). CDKs control the progression from growth phases (G₁ and G₂) to phases associated with DNA synthesis (S) and mitosis (M) (Fig. 8.2). Expression of cyclins is cell cycle dependent and control is regulated through transcriptional, translational, and posttranslational mechanisms [211]; alternatively, the expression of CDKs remains fairly constant. Specific CDC-CDK complexes facilitate progression through the various cell cycle checkpoints. Briefly, in response to extracellular growth signals, cyclin D1 is synthesized and complexes with CDK4 which initiates progression through G₁S. The cyclin D1-CDK4 complex phosphorylates RB, which dissociates from the E2F/DP1/RB complex allowing E2F-mediated transcription of cyclins A and E. Cyclin E complexes with CDK2 facilitate progression through G₁S checkpoint. Cyclin A complexes with CDK2 to allow progression through S-phase and cyclin B then complexes with CDK1 to regulate G₂M and entry into mitosis.

Unrestrained cell growth and proliferation are hallmarks of cancer [37]. Cellular functions such as apoptosis, senescence, differentiation, and proliferation are all integrally linked with the cell cycle regulatory machinery [212]. Alterations in this machinery facilitate the biological potential and aberrant behavior of cancer cells. Abrogating proliferative signaling by targeting specific driver proteins may provide new targets for therapeutic intervention in HNSCC. Traditional chemotherapies, such as antimitotics, form the mainstay chemotherapy in many solid tumor types. However, these agents are relatively indiscriminant in their effects on tumor and normal cells and adverse effects are significant. Agents that selectively target mitosis-regulating proteins that are differentially expressed in tumor (relative to normal tissues) could enhance the armamentarium of adjuvant treatments in HNSCC. Targets that fit this profile, in phase II of clinical development in HNSCC, include PLK1, WEE1, and CDK4/6 (Fig. 8.2).

The majority of cancer research examines the genetic/epigenetic alterations and oncogenic signaling pathways that drive malignant transformation. Accordingly, most emerging molecular targeted therapies for HNSCC target the malignant epithelium. However, the last three decades have elucidated that malignantly transformed cells do not act independent of the host [243–246]. Alternatively, tumors behave as organs that co-opt the surrounding phenotypically and genetically normal tumor microenvironment (TME) to cooperate in their malignant schema (Fig. 8.3) [245]. The TME includes the surrounding mesenchyme (tumor-associated fibroblasts [TAFs] and extracellular matrix [ECM]), vasculature (blood and lymphatic vessels), and cancer-associated inflammatory infiltrate [243]. The intricate web of exploitation directed by tumor cells on the TME contributes considerably to tumor heterogeneity and response (or lack of response) to chemotherapies [246, 247]. Contributions of the TME to cancer progression and heterogeneity include: supporting proliferative signaling, escaping growth inhibition, defying programmed cell death, permitting mitotic immortality, de novo angiogenesis, stimulating invasion and metastasis, reprogramming energy metabolism, and evading immune destruction [244]. Interfering with the tumor-TME relationship may provide additional weapons to the armamentarium of targeted anticancer agents currently being investigated. Agents that target the TME currently under clinical investigation have been focused to perturb angiogenesis (e.g., VEGF and VEGFR), signaling from the tumor stroma (HGF) (discussed above) and tumor-associated inflammation. Herein we highlight the angiogenesis pathway and immunomodulatory targets that are ongoing interests for pathway-targeted strategies for the treatment of HNSCC (Fig. 8.3).