KIT gene in pediatric osteosarcomas: Could it be a new therapeutic target?

In our previous study, a frequent rearrangement at 4q12 has been identified by allelotyping in our large and homogeneous population of pediatric osteosarcomas and it was significantly linked to c-kit protein overexpression. To confirm and understand the involvement of KIT in this tumor, the next step of the study was designed to detect the potential mutations of KIT gene by sequencing the frequently mutated exons 6, 8, 10, 11, 13, 17 and 21 and, in case of unmutated samples, to confirm the genomic amplifications of the wild-type receptor by real-time quantitative PCR (QPCR). A new microsatellite and QPCR targeting PDGFRA was also added to check the accuracy of the 4q11-12 locus. These techniques were performed in 74 pediatric high-grade osteosarcomas treated with the OS94 protocol. Surprisingly, no mutations were found, but, only DNA amplification of KIT gene in the entire population. PDGFRA gene QPCR revealed an unexpected result of predominant deletions in the rearranged tumors. All these results confirm the major role of the 4q11-12 locus and specifically the involvement of c-kit wild-type receptor overexpression in pediatric osteosarcomas and leads us to believe that inhibitors targeting this receptor could have a therapeutic effect in a selected group of patients.     

Methionine dependency of cancer cells: a new therapeutic approach?

Metabolic abnormalities of tumor cells offer opportunities of therapeutic targeting. In contrast to normal cells, tumor cells have absolute requirement for methionine (Met), an essential amino acid. Many molecular mechanisms have been considered to explain Met dependency. Several approaches have been used To reduce Met in vivo. As the main Met source was food, synthetic Met free diet were widely used. Alternatively, Met restriction was archived by the use of Met analogs or enzymatic degradation by methioninase. In animal models, Met restriction permit to limit tumor growth and to reduce tumor volume. However, interruption of Met restriction induce the regrowth of tumor. Moreover Met restriction induce several cells modifications suggesting its use in association with conventional chemotherapy. Preclinical studies have shown synergistic effect of the association of Met restriction and different cytostatic agents. Currently, few clinical investigations have been realised to test this therapeutic strategy.     

VAV1: a new target in pancreatic cancer?

Pancreatic ductal adenocarcinoma (PDA) is arguably the most lethal malignancy in the United States. Despite the identification of many molecular alterations in PDA, this information has not translated into effective therapeutic strategies to date. A recent report in Cancer Cell (Fernandez-Zapico et al, Cancer Cell 2005, 7:39-49) reveals an unexpected role for the hematopoietic-specific RhoGEF VAV1 in pancreatic tumorigenesis, where ectopic expression of VAV1 as a result of promoter demethylation was identified in the majority of established cell lines and PDA tissue samples. Importantly, VAV1 expression was functionally required for optimal proliferation, transformation and survival of pancreatic cancer cell lines. This study provides the first evidence of VAV1 promoter demethylation as an event in cancer progression, suggesting that aberrant signaling pathways driven by VAV1 are potential therapeutic targets in PDA.     

Obesity hormone leptin: a new target in breast cancer?

Leptin is a multifunctional hormone produced mainly by the adipose tissue and involved in the regulation of food intake and energy balance. In addition, leptin can stimulate mitogenic and angiogenic processes in peripheral organs. Because leptin levels are elevated in obese individuals and excess body weight has been shown to increase breast cancer risk in postmenopausal women, attempts have been made to evaluate whether leptin can promote breast cancer. Data obtained in cell and animal models and analyses of human breast cancer biopsies indeed suggest such an involvement. Furthermore, a recent report clearly shows that targeting leptin signaling may reduce mammary carcinogenesis. Thus, leptin should become a new attractive target in breast cancer.     

What are regulatory T cells (Treg) regulating in cancer and why?

The role regulatory T cells (Treg) play in cancer development and progression is not clear. Earlier evidence suggested that CD4(+)FOXP3(+)CD25(high) Treg accumulate in tumors and the peripheral blood of patients with cancer and through suppression of anti-tumor immune responses promote tumor growth. However, more recent data indicate that in certain cancers, such as colorectal carcinoma (CRC), Treg suppress bacteria-driven inflammation which promotes carcinogenesis and thus benefit the host. Treg appear to play a dual role in cancer. This might explain why the frequency and functions of Treg are associated with a poor prognosis in some cancers but with favorable outcome in others. The clinical and prognostic significance of Treg in cancer depends on environmental factors, including infectious agents, tumor-derived products and locally-produced cytokines, which shape the nature of immune responses, including Treg generation, recruitment and survival. Adaptive or inducible (i) Treg or Tr1 are the major subset(s) of Treg present in cancer. These iTreg are a distinct subset of regulatory cells that phenotypically and functionally differ from FOXP3(+) natural (n) Treg responsible for peripheral tolerance. They mediate powerful suppression of effector T cells via diverse mechanisms, produce immunosuppressive cytokines, notably TGF-β as well as prostaglandin E2 and adenosine, and are resistant to apoptosis or oncological therapies. Strategies for silencing of Tr1 in patients with cancer will require novel approaches that can selectively deplete these cells or block molecular pathways they utilize.     

Dormant tumor cells as a therapeutic target?

Tumor dormancy is characterised by the persistence of residual tumor cells for long periods. Recurrence from minimal residual disease is a major cause of cancer death. Thus, understanding how cancer cells become and remain dormant, may lead to new strategies to prevent relapse. Evidence has emerged that a balance exists between host and dormant tumor cells. Cross-talk between tumor cells and their micro-environment, angiogenesis, and anti-tumor immune response participate in the control of dormant tumor cells. Tumor cells have several mechanisms of maintaining equilibrium, and immune escape, including expression of immuno-regulatory molecules (e.g., increased expression of B7.1 and B7-H1); epigenetic modifications (e.g., silencing of the SOCS1 gene, de-regulating the JAK/STAT pathway); and autocrine loops. These new findings offer new opportunities to design specific treatments, to modify the balance in favor of the host immune response.     

Will cancer stem cells provide new therapeutic targets?

This review presents a brief synopsis of recent progress in the area of cancer stem cells, with emphasis on leukemia and breast cancer, and discusses potential limitations to accomplishing the ultimate goal of eradicating residual disease in cancer.     

Male breast cancer: a special therapeutic problem. Anything new? (Review)

Carcinoma of the male breast (MBC) is an uncommon phenomenon, accounting for <1% of all malignancies in man. It represents a biologically heterogeneous disorder, and its clinical course may vary from indolent and slowly progressive to rapidly metastatic disease. Most of our current knowledge regarding its biology, natural history, and treatment strategies has been extrapolated from its female counterpart. Information regarding prognostic relevance of new molecular markers is limited. At the European Institute of Oncology we performed a study showing data in which p21Waf1 and p27Kip1 proteins were evaluated in a series of male breast cancer patients. Our data suggest that the immunohistochemical evaluation of p21Waf1 and p27Kip1 expression in male breast carcinomas may be a further useful marker for selecting patients who express functional proteins that can be predictive for the most efficient endocrine response. Moreover, searching for more conservative treatment, we introduced in our clinical practice sentinel node biopsy, and if present, sentinel node biopsy of the internal mammary chain. The potential clinical implications of complete nodal staging are far-reaching, and give us a major new opportunity to stratify male patients with breast cancer for appropriate surgery as well as giving valuable prognostic information. Male breast cancer has biological differences compared with female breast cancer. It responds to hormonal manipulation and chemotherapy, but optimal treatment regimens in males are unknown. By analogy to the female breast cancer, post-mastectomy radiotherapy should be proposed in case of advanced T stage and/or lymph node positivity (considering the small volume of the male mammary gland, we suggest post-mastectomy irradiation in case of T >1 cm and/or presence of >1 metastatic axillary lymph node). Breast conserving surgery, performed in selected cases of male breast cancer, should be always followed by radiotherapy. Despite a wealth of small retrospective studies on MBC, its rarity means there is a lack of prospective randomized controlled treatment trials, which needs to be addressed if significant advances are to be made in the treatment of this unusual challenging disease.     

BAD: a good therapeutic target?

The major goal in cancer treatment is the eradication of tumor cells. Under stress conditions, normal cells undergo apoptosis; this property is fortunately conserved in some tumor cells, leading to their death as a result of chemotherapeutic and/or radiation-induced stress. Many malignant cells, however, have developed ways to subvert apoptosis, a characteristic that constitutes a major clinical problem. Gilmore et al. recently described the ability of ZD1839, a small-molecule inhibitor of the epidermal growth factor receptor (EGFR), to induce apoptosis of mammary cells that are dependent upon growth factors for survival. Furthermore, they showed that the major effector of the EGFR-targeted therapy is BAD, a widely expressed BCL-2 family member. These results are promising in light of the role of the EGFR in breast cancer development.     

Could p53 be a target for therapeutic suppression?

The function of p53 has been traditionally viewed in the context of its tumor suppressor activity. In fact, the p53-dependent growth arrest and apoptosis, occurring in response to a variety of stimuli, act to protect the organism from cancer by eliminating potential tumor precursors. However, the same functions of p53 could determine severe damage of normal tissues as a consequence of genotoxic stress associated with anti-tumor therapy. This makes p53 a potential target for therapeutic suppression with the purpose of rescuing normal tissues from the side effects of cancer treatment. We analyze the accumulated information regarding the role of p53 in acute and long-term consequences of genotoxic stress in vivo. Comparison of p53 wild type and p53-deficient mice indicates that p53, in fact, determines massive apoptosis occurring shortly after gamma irradiation in radiosensitive tissues. Sites of apoptosis match the tissue-specific pattern of p53 mRNA expression indicating that p53 regulation at mRNA level is a determinant of acute radiosensitivity of tissues. In the hematopoietic system, radiation-induced death of both differentiating and stem cells strongly depends on p53, suggesting that p53 suppression would decrease damage and promote faster recovery of hematopoiesis after anti-cancer therapy. However, p53 does not effect the recovery of radiosensitive epithelia since their stem cells, in contrast to differentiating cells, die in a p53-independent manner. The validity and potential complications of therapeutic suppression of p53 in cancer treatment and under other stressful conditions are discussed in relation to the p53 functions in normal development.     

Autocrine stimulation of cell proliferation in colonic carcinoma: a biological curiosity or a new therapeutic target?

Chemotherapy has little efficacy in the treatment of advanced colorectal carcinoma. Biological investigation has made evident several autocrine stimulation loops; the best documented one involves epidermal growth factor (EGF): this growth factor stimulates cell proliferation and cell secretion of proteolytic enzymes. Suramin and somatostatin are able to disrupt these loops of stimulation. Clinical studies performed with octreotide, a somatostatin analogue, and suramin have been unsuccessful until now.     

Can lung cancer stem cells be targeted for therapies?

Lung cancer is the leading cause of cancer death, with a poor prognosis. Lung cancer stem cells (CSCs) are proposed as one of therapeutic targets for lung cancer. It is important to understand the exact role of lung CSC subpopulations in tumor initiation, recurrence, drug resistance and metastasis and explore biomarkers, signaling pathways and differentiation regulation specific to lung CSCs. Numerous measures targeting lung CSCs, e.g. genomics, proteomics and bioinformatics, have been used to investigate molecular mechanisms, eradicate cancer cells, and improve patient outcome. The present review overviewed the biological functions, biomarkers, signal pathways, differentiation regulation, genomics and proteomics, targeting roles of lung CSCs and related information on other CSCs as references. There are still a number of challenges to translate the research and understanding of lung CSCs to clinical applications and therapies, identify lung CSCs-specific and dynamic network biomarkers, study lung CSCs isolated from human samples, and clarify the source of lung CSCs. It is necessary to design effective therapies to target CSC biomarkers and signaling pathways, reverse drug resistance and induce differentiation of lung CSCs. Thus, lung CSCs as one of therapeutic target candidates for lung cancer need global forces and databases to integrate the genes, proteins, receptors, signal pathways and functions with clinical informatics and phenotypes together.     

Notch signaling as a therapeutic target for breast cancer treatment?

Aberrant Notch signaling can induce mammary gland carcinoma in transgenic mice, and high expressions of Notch receptors and ligands have been linked to poor clinical outcomes in human patients with breast cancer. This suggests that inhibition of Notch signaling may be beneficial for breast cancer treatment. In this review, we critically evaluate the evidence that supports or challenges the hypothesis that inhibition of Notch signaling would be advantageous in breast cancer management. We find that there are many remaining uncertainties that must be addressed experimentally if we are to exploit inhibition of Notch signaling as a treatment approach in breast cancer. Nonetheless, Notch inhibition, in combination with other therapies, is a promising avenue for future management of breast cancer. Furthermore, since aberrant Notch4 activity can induce mammary gland carcinoma in the absence of RBPjκ, a better understanding of the components of RBPjκ-independent oncogenic Notch signaling pathways and their contribution to Notch-induced tumorigenesis would facilitate the deployment of Notch inhibition strategies for effective treatment of breast cancer.     

XMRV: a new virus in prostate cancer?

Several recent articles have reported the presence of a gammaretrovirus, termed "XMRV" (xenotropic murine leukemia virus-related virus) in prostate cancers (PCa). If confirmed, this could have enormous implications for the detection, prevention, and treatment of PCa. However, other articles report failure to detect XMRV in PCa. We tested nearly 800 PCa samples, using a combination of real-time PCR and immunohistochemistry (IHC). The PCR reactions were simultaneously monitored for amplification of a single-copy human gene, to confirm the quality of the sample DNA and its suitability for PCR. Controls showed that the PCR assay could detect the XMRV in a single infected cell, even in the presence of a 10,000-fold excess of uninfected human cells. The IHC used 2 rabbit polyclonal antisera, each prepared against a purified murine leukemia virus (MLV) protein. Both antisera always stained XMRV-infected or -transfected cells, but never stained control cells. No evidence for XMRV in PCa was obtained in these experiments. We discuss possible explanations for the discrepancies in the results from different laboratories. It is possible that XMRV is not actually circulating in the human population; even if it is, the data do not seem to support a causal role for this virus in PCa.     

β1-integrin: a potential therapeutic target in the battle against cancer recurrence

Primary cancer treatment, involving both local and often systemic adjuvant therapy, is often successful, especially if the cancer is detected at an early stage of progression. However, for some patients, the cancer may recur either locally or as distant metastases, in some cases many years after apparently successful primary treatment. Significant tumor dormancy has been documented in several cancers, such as breast, melanoma, and renal cancer. Tumor dormancy has long been recognized as an important problem in management of cancer patients. Recent work has clarified biologic aspects of tumor dormancy and has shown that dormant tumor cells may be resistant to cytotoxic chemotherapy and radiation. This work has led to recognition of a key role for β1-integrin in regulating the switch from a dormant state to active proliferation and metastasis. Here we discuss the role of β1-integrin and its signaling partners in regulating the dormant phenotype. We also consider possible therapeutic approaches, such as small molecules or antibodies (ATN-161, volociximab, and JSM6427), directed against β1-integrin signaling to target dormant cancer cells and to prevent metastatic recurrence.