Current Cancer Drug Targets - Volume 9, Issue 7, 2009

We hope that you will find the reviews in this special issue of Current Cancer Drug Targets informative and stimulating so that together we can contribute to found new strategies for treatment of cancer and its effects. Cancer metastasis is a complex cascade of events that includes detachment of metastatic cells from the primary tumour and invasion of the surrounding interstitial stroma, entry of the metastatic cells into the circulatory system (intravasation), arrest in distant organs via interactions of tumour cells with platelets, macrophages and the vascular and lymphatic endothelium, and exit from the bloodstream (extravasation) which thereby gain tumour cells access to the surrounding parenchyma of the target organ where they thrive to form secondary tumours. The cells comprising the premetastatic niche express integrins, which provide a permissive environment for the migrating tumor cells. In addition, various growth factors and cytokines in the bone marrow such as endothelin, transforming growth factor (TGF)-β, IL-6, and IL-8 serve as paracrine regulators of the initial growth of metastatic tumor cells. The interaction of receptor molecules in the bone marrow stroma with the integrins that are over-expressed on the tumor cells promotes colonization of circulating malignant cells in the bone marrow. As described by P. Clezardin, αvβ3 integrin facilitates the colonization of bone by osteotropic cancer cells. Moreover, osteoclasts (the bone-resorbing cells) also express αvβ3 integrin. Bone desease is the hall-mark clinical feature of several cancers, as multiple myleoma, sarcoma, prostate, lung and breast cancer.

Therapy with aminobisphosphonate (N-BPs), and zoledronic acid (ZOL) especially, has become a standard of care for patients with malignant bone disease. In addition, preclinical and preliminary clinical data suggest that N-BPs exert their direct or indirect anti-tumour effects on cancer growth factor release, cancer cell adhesion, invasion and viability, cancer angiogenesis and cancer cell apoptosis. Here, we will discuss the molecular mechanisms of the antitumour effects induced by ZOL. Despite their well-established in vitro anti-tumour effects N-BPs have not clear in vivo anti-tumour activity in humans. The bases of these discrepancies will be discussed in the text with a special focus on the pharmacokinetic limits of N-BPs. Moreover, the following molecular and pharmacological strategies in order to overcome N-BPs limitations will be described: i) development of pharmacological combinations with other biological agents; ii) finding of new molecular targets of N-BPs; iii) development of new pharmacological formulations of N-BPs. Finally, a new scenario of integrated bio-medicine and pharmacology will be depicted in order to drive the optimization of anti-cancer activity of N-BPs.

Integrins constitute a family of cell surface receptors that are heterodimers composed of noncovalently associated α and β subunits. Integrins bind to extracellular matrix proteins and immunogobulin superfamily molecules. They exert a stringent control on cell migration, survival and proliferation. However, their expression and functions are often deregulated in cancer, and many lines of evidence implicate them as key regulators during progression from primary tumor growth to metastasis. Here, we review the role of integrins in bone metastasis formation and present evidence that the use of integrin-targeted therapeutic agents may be an efficient strategy to block tumor metastasis.

Bisphosphonates are extensively used to treat cancer-induced bone disease in a range of solid tumours and multiple myeloma, where they reduce the incidence of skeletal related events and improve patients' quality of life. Recent reports indicate that bisphosphonates may also prevent recurrence of breast cancer at peripheral sites, suggesting that these drugs may have anti-tumour effects outside the skeleton. Anti-tumour effects of several bisphosphonates have been reported in a range of tumour cell types in vitro. These positive results have subsequently been supported by investigations of effects of bisphosphonates on tumour growth in vivo, both in bone and at peripheral sites. A reduction of tumour burden and also in cancer-induced bone disease has been reported following bisphosphonate treatment in several model systems, including breast and prostate cancer, osteosarcoma and multiple myeloma. In addition, bisphosphonates have been shown to significantly reduce growth of human tumour cells (including breast, prostate, lung and mesothelioma) implanted subcutaneously in immunocompromised mice. However, the majority of in vivo studies showing a reduction in bone disease and reduced tumour burden have used high doses and frequent administration of bisphosphonates, and the clinical relevance of these data have therefore been the subject of considerable debate. Bisphosphonates may hold greater promise as anti-tumour agents when used in combination with cytotoxic drugs, and several in vivo studies have reported substantial increased inhibition of tumour growth and improved survival when bisphosphonates have been added to standard chemotherapy regimens. This review will summarise the published data on anti-tumour effects of bisphosphonates from in vivo models, alone and in combination with other anti-cancer agents, and highlight the main lessons learned and future challenges in this field.

Bisphosphonates are the standard of care for preventing skeletal morbidity and treating hypercalcemia of malignancy in patients with bone metastases. Zoledronic acid (intravenous; 4 mg monthly) is approved to prevent skeletalrelated events (SREs) in patients with bone metastases from several tumor types, and can improve survival in some subsets of patients with skeletal metastases and high baseline bone turnover. In the adjuvant setting, bisphosphonates have shown clinical efficacy for preventing cancer treatment-induced bone loss and promise for reducing disease recurrence. For example, early studies of clodronate showed the potential for bisphosphonates to prevent bone metastases and prolong survival, but results with clodronate have been inconsistent. Recently, the more active bisphosphonate zoledronic acid (4 mg every 6 months) prevented bone loss and significantly reduced the risk of disease-free survival events by 36% (P = .01) compared with adjuvant endocrine therapy alone in a large phase III trial (N = 1,803) in premenopausal women with early breast cancer. Notably, these benefits were not limited to bone, because the addition of zoledronic acid reduced disease recurrence at all sites. Similarly, twice-yearly zoledronic acid has reduced disease recurrence in large phase III trials in more than 1,600 postmenopausal women with early breast cancer. Several ongoing trials (involving more than 20,000 patients altogether) are evaluating the efficacy of bisphosphonates for prevention of metastases in breast, prostate, and lung cancers; and multiple myeloma. Results from these studies are likely to expand the role of bisphosphonates, especially zoledronic acid, in the adjuvant therapy setting.

This system constituted of the Receptor Activator of nuclear Factor-kB Ligand (RANKL), the Receptor Activator of Nuclear Factor-kB (RANK) and by the decoy Receptor Osteoprotegerin (OPG) plays a central role in bone resorption. Denosumab (AMG 162) is an investigational fully human monoclonal antibody with a high affinity and specificity for RANKL.This review will critically describe and discuss the recent results of clinical trial investigating denosumab in different settings of medical oncology. In particular, we will report the recently published data of clinical trials investigating denosumab in prevention of cancer treatment induced bone loss (CTIBL), in prevention of skeletal related events (SREs) in bone metastatic patients and the ongoing studies in prevention of disease recurrence in the adjuvant setting of solid tumours. The clinical data that will be reported in this review represent the first step in a path that will conduct us to explore new horizons in the field of bone health care in cancer patients.

The treatment of sarcoma urgently requires new, innovative therapeutic strategies. The most recent improvements in the cure of patients with localized disease have been achieved by dose-intensification, in turn paying the price of acute severe toxicity and secondary malignancies. Keeping side-effects to a minimum is an important goal for pediatric patients and this may be achieved by combining standard cytotoxic chemotherapy with targeted approaches. In addition, after first-line therapy, very limited treatment options remain for patients with disease progression, who, like patients with metastasis at diagnosis, are in urgent need of more effective drugs. The present review highlights key examples of target identification in bone sarcomas, including chimeric oncoproteins, insulin-like growth factor receptor (IGF-IR), and tumor/ microenvironment interactions. The review identifies questions and concerns that still need to be addressed before proceeding to safe clinical trials with agents against these promising new targets.

Bone disease (BD) is the hall-mark clinical feature of multiple myeloma (MM), accounting up to 60% of patients with bone pain at diagnosis and 60% with a pathologic fracture during the course of their disease. Experimental models, which recapitulate in vivo the human bone marrow microenvironment (HBMM) in immunodeficient mice have been recently developed as valuable tool for the study of MM pathophysiology as well as the experimental treatment of BD. At present, bisphosphonates are the mainstay treatment of MM-related BD. The growing information on the cellular and molecular bases of BD as well as the availability of novel anti-resorptive agents, such as the IgG1-anti-RANKL (AMG 161) Denosumab, are now depicting a new scenario where the treatment will be afforded by the use of different agents. Furthermore the availability of highthroughput molecular profiling approaches, including DNA microarrays and proteomics, is likely to provide new platforms for patients stratification and treatment individualization on specific targets. It is now the right time for a therapeutical approach which is rationally based on the complexity of the biopathology of MMrelated BD.

Appropriate subcellular localization of proteins is crucial for regulating their functions. Both p53 and the BH3- only Bid play roles in the development and the treatment of hepatocellular carcinoma (HCC). They both participate in the cross talk of cell cycle arrest and apoptosis in response to DNA damage. However, some important issues related to their pathways are not yet resolved. Bid genomic loci contain p53-binding DNA response elements and Bid can mediate p53- dependent transactivation. Here, we showed that etoposide-induced DNA damage could significantly induce p53 and Bid nuclear export. When cells were stimulated by etoposide, p53 could, through the association with Bid, cause translocation of Bid from the nucleus to the cytoplasm and on to its ultimate location in the mitochondria. p53 was physically associated with Bid, and both p53 and Bid cooperatively promoted cell death induced by etoposide. Knockdown of Bid expression notably attenuated cell death induced by etoposide and also released p53 from the mitochondria. These findings reveal a novel mechanism by which p53 is associated with Bid in the nucleus to facilitate exportation of Bid to the mitochondria and induce apoptosis in response to etoposide-induced DNA damage in HCC.

Prostate cancer possesses its unique feature of low proliferation rate and slow growth. Ca2+-induced apoptosis is not dependent on cell cycle progression and targeting this pathway could circumvent the problems encountered using current cytotoxic chemotherapies for prostate cancer. Hypoxia-inducible factor 1α (HIF-1α) is another novel cancer drug target and inhibitors of hypoxia-response pathway are being developed. Digoxin and other cardiac glycosides, known inhibitors of the alpha-subunit of sarcolemmal Na+K+-ATPase, were recently found to block tumor growth via the inhibition of HIF-1α synthesis. Thus, cardiac glycosides disrupt two important cellular pathways and, therefore, may be useful as an anticancer therapy. This review will focus on HIF-1α and calcium signaling as novel cancer drug targets in prostate cancer. The possible application of digoxin and other cardiac glycosides in cancer therapeutics especially in prostate cancer is discussed.