Cancer Chemoprevention

Prevention-Therapy Convergence

Molecular-targeting research is blurring the distinction between malignancy and premalignancy and between cancer therapy and prevention. A new generation of targeted drugs with acceptable therapeutic indices for prevention and therapy is emerging from the molecular study of neoplasia (IEN and cancer), drug effects on relevant pathways, and cancer risk/prognosis. Targeted drugs can move from therapy to prevention (exemplified by tamoxifen, aromatase inhibitors, and EGFR inhibitors) or vice versa (celecoxib). It is likely that tamoxifen both prevented and treated subclinical cancer in the Breast Cancer Prevention Trial (BCPT) and adjuvant breast cancer trials. Always problematical, the distinction in cancer survivors between a second primary tumor (SPT), which is a prevention endpoint, and recurrence, which is a therapy endpoint, has been blurred further by molecular studies in breast and head and neck neoplasia. The distinction between cancer and IEN is blurred in definitively treated oral cancer patients who develop IEN at a very high risk of a new cancer because of genomic instability and loss of heterozygosity (LOH ). Furthermore, it is very difficult to determine if the new cancer developing in these patients is an SPT or a recurrence. Rigorous clinical determinations of SPT or recurrence following curative treatment of head and neck cancer have been questioned by genetic profiling that revealed substantial molecular ambiguity regarding the origins of the subsequent cancers. For example, more than 50% of the clinically defined SPTs were molecularly determined to be recurrences (i.e., to have genetic profiles consistent with clonal spread of the original tumor ).

In recent years, the paradigm in which “at-risk” tissue is visualized by autofluorescence has evolved and progressed from the lungs into the oral cavity as well as other major organ sites. New developments coupling autofluorescence with digital imaging/processing have the potential to become an important diagnostic adjuvant and make a significant impact on detection and evaluation of tissue alterations associated with neoplastic development. An exciting new imaging modality recently provided proof-of-principle in the ability of noninvasive optical imaging to accurately identify neoplastic tissue and premalignant lesions. Using novel biomedical optics technology, microvascular blood content in the proximity of a neoplasia can be measured and evaluated for field effects and can play a potential role in distinguishing various stages of neoplasia.

Convergent Trial Designs

Two convergent trial designs involving molecular-targeted agents are (1) a Phase I design in which toxicity and pharmacodynamic effects (e.g., optimal biologic doses) are assessed to determine the dose of an agent for subsequent Phase II testing in either prevention or therapy and (2) a therapy design with embedded prevention endpoints (e.g., IEN) for agents with preventive potential based on mechanistic and safety characteristics. The Phase I design can include assessments of pharmacodynamic effects on tumor and surrounding or surrogate tissue. The embedding design can include Phase II or III trials in cancer settings with a prevalent IEN, for example, rectal aberrant crypt foci (ACFs) in single-agent colon cancer trials. ACFs can be identified by magnifying endoscopy (e.g., flexible sigmoidoscopy in the rectum) and are thought to be precursors of adenomas. ACFs often show Apc loss, K-ras mutations, and EGFR and erbB2 upregulation, and the number, size, and dysplastic features of ACFs correlate with the number of adenomas. ACFs appeared to be suppressed by NSAIDs in observational studies, by EGFR TKIs in preclinical studies, and by metformin in an early clinical trial. Another embedded convergence approach is to assess at-risk tissue in adjuvant trials—for example, bronchoscopic studies in adjuvant lung cancer trials. A recent study detected EGFR TK domain mutations and increased estrogen receptor expression in histologically normal lung tissue surrounding a primary lung adenocarcinoma with EGFR mutations. This apparent field effect raises important biologic issues and may help identify patients more likely to benefit from adjuvant therapy with EGFR TKIs. Drug activity in high-risk IEN is relevant to the therapy setting; prevention trials in high-risk settings and therapy trials have similar sizes, durations, costs, and ethical considerations (high cancer risk justifies potential adverse drug effects, as does cancer prognosis ). The highest risk IENs, such as familial adenomatous polyposis and oral IEN with LOH, are promising settings for convergent drug development.

Short-term trials in patients before a scheduled surgery also can be used for early-phase convergent drug development, as illustrated by recent studies of EGFR TKIs in breast neoplasia. The EGFR TKIs gefitinib and erlotinib reduced cell proliferation in randomized presurgical trials in women with ductal carcinoma in situ or early-stage breast cancer. Although not involving therapy, a novel convergent approach is to embed prevention endpoints in a screening study. A recent randomized trial of inhaled budesonide was embedded within a spiral computed tomography (CT) screening study involving high-risk people with peripheral lung nodules (presumed precursors of adenocarcinoma). Although this study yielded negative results, the treatment was well tolerated. This novel trial design was the first formal clinical assessment of preventive effects on adenocarcinoma precursors in the peripheral airway.

Promising Convergent Targets and Drugs

Many promising targets for cancer prevention and therapy are in preclinical studies related to drugs currently in clinical testing ( Table 58-1 ). Some of the major signaling pathways with promising molecular targets are discussed in the following sections.

EGFR Signaling

EGFR is upstream of several major targets/pathways, including COX-2, PI3K, and vascular endothelial growth factor (VEGF), and has complex interactions with retinoic acid signaling and the IGF axis (discussed later). (EGFR also is upstream of cyclin D1, signal transducer and activator of transcription-3 [STAT3], and Src.) The importance of EGFR as a prevention-therapy target is illustrated in lung carcinogenesis. High EGFR ( ErbB1 ) gene copy number and protein expression occur in lung IEN and have been associated with a poor prognosis in resected non–small-cell lung cancer. EGFR inhibitors have activity in a mouse lung cancer prevention model and in non–small-cell lung cancer therapy (in association with high EGFR). EGFR TK domain mutations (which are associated with EGFR TKI response) have been detected in high-risk nonmalignant lung tissue. EGFR is a potential target for convergent drug development in several sites and, as discussed in the following paragraphs, EGFR signaling has complex pathway interactions and feedback loops that make it very promising for use in combination targeting approaches.

Polyunsaturated Fatty-Acid Metabolic Signaling

Membrane phospholipids including arachidonic acid (AA) and linoleic acid (LA) are converted by a series of enzymes to a variety of eicosanoids, which differ markedly in their biological activities. The cyclooxygenase (COX) pathway leads mostly to the generation of prostaglandins (PGs), prostacyclins, and thromboxanes (TXs), whereas the lipoxygenase (LOX) pathway leads to the formation of leukotrienes, hydroxyeicosatetraenoic acids (HETEs), lipoxins, and hydroxyoctadecadienoic acid (HODEs). These biologically active lipids orchestrate the complex interactions between transformed epithelial cells and the surrounding stromal cells and play crucial roles in chronic inflammation and cancer (as reviewed in Reference ). The enzymes involved in AA metabolism (COX1/2, 5-LOX, and 12-LOX) have been among the most extensively studied targets for anticancer therapy and prevention. In addition to its other effects, aspirin (a nonselective NSAID) has been shown to be an especially effective chemopreventive agent for colorectal neoplasia, through its actions as an inhibitor of the COX-2 pathway, which is overexpressed in 80% to 85% of colorectal cancers. The LOX pathway enzymes (5-LOX, 12-LOX, and 15-LOX-1/2) also have an important role in tumor progression and survival. The 15-LOX-1 enzyme and its products (15-S-HETE and 13-S-HODE) induce apoptosis, and losses of 15-LOX-1 expression and enzymatic activity were the only significant changes in LOX metabolism that related to the loss of cell differentiation and apoptosis in colon cancer cells in vitro and in polyps of familial adenomatous polyposis patients. Pharmacologic or genetic restoration of 15-LOX-1 induces apoptosis and suppresses tumorigenesis in vivo. 15-LOX-1 interacts with GATA-6, protein kinase G, histone deacetylase (HDAC), methyltransferase (upstream 15-LOX-1 regulators), and PPAR-δ and -γ (downstream 15-LOX-1 mediators) to induce apoptosis and suppress carcinogenesis. 13-S-HODE downregulates PPAR-δ to activate PPAR-γ and induce apoptosis, indicating that polyunsaturated fatty acid oxidative metabolism can influence the balance between PPAR-δ and PPAR-γ. Understanding the roles of prostaglandins and leukotrienes in epithelial-derived tumors and their microenvironment may help to develop cancer biomarkers and chemopreventive and/or therapeutic agents with minimal side effects compared to NSAIDs.

Nuclear Receptor Signaling

Members of the nuclear receptor (NR) superfamily of ligand-dependent transcription factors are implicated in a broad spectrum of physiologic and pathophysiologic processes. As well, NRs have widespread anti-inflammatory roles in the cells of the immune system that contribute to the tumor microenvironment. Evidence exists for an increased risk for cancer development among patients with chronic inflammatory diseases such as diabetes or ulcerative colitis. That NRs and their ligands play a prominent role in modulating the microenvironment and inhibiting tumor-promoting inflammation makes them promising therapeutic targets for high-risk populations when used in combinatorial or chemopreventive strategies.

Promising convergent targets also are emerging from studies of retinoid signaling through retinoic acid receptor (RAR) and retinoid X receptor (RXR) types, subtypes, and isoforms. Retinoids modulate cell growth and gene expression by activating nuclear RARs and RXRs, each of which exists in several isoforms and possesses distinct functions. For example, the RAR-β ₂ subtype is a putative tumor suppressor, whereas RAR-β ₄ has oncogenic properties. RAR-β ₂ suppresses COX-2 expression and frequently is methylated in tobacco-related and other neoplasias. Recent studies have identified a novel RAR-β ₂ –induced gene, RRIG1, which encodes a cell membrane protein that binds to and inhibits RhoA activity and mediates the effects of RAR-β ₂ on cell growth and gene expression. These findings highlight molecular pathways involving RAR-β ₂ , RRIG1, COX-2, and RhoA—all of which are promising convergent targets.