Cancer Chemoprevention

Targeting the insulin-like growth factor (IGF) axis continues to be an important area of research for both prevention and therapy, as illustrated by recent data in the aerodigestive tract. Elevated levels of IGF-1 and reduced levels of IGF binding protein 3 (IGFBP-3) are associated with increased risk and poor prognosis in lung and other cancers ⁶⁰ ; IGF-1 is a mitogen for a number of neoplastic cells types. The IGF-1 receptor (IGF-1R) is activated during lung carcinogenesis in vitro and in vivo in animals. Targeting IGFR and its downstream pathways (e.g., by the use of IGFBP-3) inhibits survival of premalignant and malignant bronchial epithelial cells and vascular endothelial cells, decreases tumor growth and angiogenesis, and for this reason may be effective for cancer chemoprevention. ⁶¹ However, several recent Phase III chemotherapy trials using IGF-1R-targeting antibodies to target late-stage solid tumors have failed to demonstrate signs of clinical efficacy, ⁶² suggesting that the need to identify potential biomarkers that could help parse out patients who would benefit most is critical. Despite the poor therapeutic outcome with the anti-IGF1R trials, encouraging results from studies targeting the IGF axis in a combinatorial fashion (e.g., STAT3 or IL-6) may be an alternative strategy for chemoprevention. ⁶³

Targeting the PI3K/Akt/mTOR signaling pathway is another promising approach, especially in the lung. Tobacco carcinogens induce Akt activation and lung carcinogenesis. The Akt pathway is activated in bronchial premalignancy (both proximal airway and alveolar epithelium) in smokers and patients with lung IEN or cancer. Preclinical in vivo studies show that deguelin and myo-inositol have preventive activity in lung tumorigenesis, in part via suppressing the PI3K/Akt pathway, disrupting Hsp90 function, and inhibiting HIF-1α expression. ^64–66 The kinase mammalian target of rapamycin (mTOR) is downstream of Akt, and the mTOR inhibitor CCI-779 blocked malignant progression of premalignant lesions with activated mTOR arising in the alveoli of mice that develop lung cancer because of activated K-ras. ⁶⁷ The mechanism by which CCI-779 inhibited tumorigenesis was unexpected. These lesions were infiltrated with macrophages, shown immunohistochemically to have prominent activation of mTOR signaling. A similar pattern of macrophage infiltration occurred in human alveolar premalignant lesions (atypical alveolar hyperplasia). Treatment with CCI-779 induced apoptosis of macrophages, which coincided with the chemopreventive effect. In vitro, CCI-779 had no effect on LKR-13, a lung adenocarcinoma cell line derived from this mouse, whereas it did induce apoptosis of macrophages, and conditioned media from macrophages directly stimulated the proliferation of LKR-13 cells. In summary, mTOR is activated in lung premalignancy and is required for malignant progression in the lung. This kinase drives tumorigenesis in part through macrophages, a prominent component of the tumor microenvironment, and the antitumor effect of mTOR inhibition required the presence of the tumor microenvironment. These findings have two important implications: mTOR is a potentially important kinase target, and the tumor microenvironment is crucial in malignant progression and a source for novel targets in chemoprevention. An mTOR inhibitor also has reversed Akt-dependent prostatic IEN in transgenic mice. ⁶⁸

The angiogenic switch is a critical regulatory switch (at the level of Ras) within neoplastic cells that targets the endothelium/microenvironment or bone marrow–derived cells recruited to the neoplastic site to reverse endothelial quiescence, thus facilitating pathological angiogenesis. Dysplastic foci and microscopic tumors in various organs can remain undetectable and asymptomatic for years in the absence of inflammation and angiogenesis—both processes key targets for chemoprevention. ^74,75 Potential drugs targeting various angiogenic switch regulators such as VEGF receptors (VEGFR including VEGFR1-3), chemokine receptors (CXCR-2 and CXCR-4), miRNAs (e.g., miR-132), and matrix metalloproteinases (e.g., MMP9) can be strategized according to risk to optimize the blockage of vascularization of incipient tumors. Some of these drug targets are under clinical development in therapy as well as for prevention. ^76,77

Drugs designed to target a single pathway cannot usually combat multigenic diseases such as cancer. Combination drugs that affect multiple targets simultaneously are better at manipulating complex disease systems and are less likely to develop drug resistance. This multidrug treatment modality has become the standard of care in many important therapeutic areas. To that end, cancer chemoprevention using low-dose combinations of different agents instead of a single agent has been suggested to synergistically enhance the preventive effect with less toxicity and fewer side effects (as reviewed in Reference 78). Several promising combinations are listed in Table 58-2 , and data supporting a few of these combinations are cited here. Methyltransferase inhibitors plus HDAC inhibitors have been shown to be highly active in vitro and in suppressing lung tumorigenesis in vivo. ⁷⁹ Many studies support COX-2-inhibitor combinations, and there is extensive preclinical data suggesting that COX-2 inhibition is an attractive target for overcoming resistance to EGFR inhibition. COX-2 inhibitors plus EGFR inhibitors (e.g., in the colon) or aromatase inhibitors (in the breast) involve positive feedback loops. COX-2 inhibitors also block prostaglandin activation of EGFR and induction of aromatase, possibly allowing lower doses and less toxicity of each agent. ^80,81 In a recent report, HDAC inhibitors can increase the sensitivity of oral adenomatous squamous carcinoma cells to EGFR inhibitors (possibly via effects on the epithelial-to-mesenchymal transition). ⁸²