The HCCR oncoprotein as a biomarker for human breast cancer.

PURPOSE: HCCR oncoprotein is reported to be related to tumorigenesis, including breast cancer, functioning as a negative regulator of p53. Mice transgenic for HCCR developed breast cancers. The objective of this study was to validate the HCCR oncoprotein as a candidate biomarker for breast cancer. EXPERIMENTAL DESIGN: HCCR expression in breast cancer cells was analyzed by quantitative PCR, ELISA, immunohistochemistry, Western blotting, fluorescence-activated cell sorting, and confocal microscopy. Epitope areas were determined using mass spectrometry through the analysis of time-dependent tryptic fragment patterns of HCCR. HCCR expression profiles in breast cancer patient sera were analyzed, and correlations with clinicopathologic data and carbohydrate antigen 15-3 (CA15-3) levels were determined. RESULTS: HCCR was up-regulated in breast cancer cells and tissues. The epitope regions of HCCR recognized by monoclonal antibody (BCS-1) were HFWTPK and QQTDFLDIYHAFR. According to fluorescence-activated cell sorting and confocal microscopic analysis, BCS-1 was bound to HCCR antigen on the cell surface. Serum HCCR concentrations were measured using ELISA from 299 subjects, including 129 patients with breast cancer, 24 patients with benign breast disease, and 158 normal volunteers, and comparisons were made to CA15-3. Serologic studies revealed an 86.8% sensitivity for HCCR in breast cancer, which was higher than 21.0% for CA15-3. Eighty-six of 98 (87.8%) patients with breast cancers that were negative for CA15-3 were positive for HCCR-1. A positive response rate of 83.3% was identified even at early stages for pathologic factors in breast cancer. CONCLUSIONS: The HCCR assay has an advantage over CA15-3 in diagnosing breast cancer and detecting early stages of the disease.     

Proteasome inhibition as a novel therapeutic target in human cancer.

The 26S proteasome is a large intracellular adenosine 5'-triphosphate-dependent protease that identifies and degrades proteins tagged for destruction by the ubiquitin system. The orderly degradation of cellular proteins is critical for normal cell cycling and function, and inhibition of the proteasome pathway results in cell-cycle arrest and apoptosis. Dysregulation of this enzymatic system may also play a role in tumor progression, drug resistance, and altered immune surveillance, making the proteasome an appropriate and novel therapeutic target in cancer. Bortezomib (formerly known as PS-341) is the first proteasome inhibitor to enter clinical practice. It is a boronic aid dipeptide that binds directly with and inhibits the enzymatic complex. Bortezomib has recently shown significant preclinical and clinical activity in several cancers, confirming the therapeutic value of proteasome inhibition in human malignancy. It was approved in 2003 for the treatment of advanced multiple myeloma (MM), with approximately one third of patients with relapsed and refractory MM showing significant clinical benefit in a large clinical trial. Its mechanism of action is partly mediated through nuclear factor-kappa B inhibition, resulting in apoptosis, decreased angiogenic cytokine expression, and inhibition of tumor cell adhesion to stroma. Additional mechanisms include c-Jun N-terminal kinase activation and effects on growth factor expression. Several clinical trials are currently ongoing in MM as well as several other malignancies. This article discusses proteasome inhibition as a novel therapeutic target in cancer and focuses on the development, mechanism of action, and current clinical experience with bortezomib.     

c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention

Receptor tyrosine kinase (RTK) targeted agents such as trastuzumab, imatinib, bevacizumab, and gefitinib inhibitors have illustrated the utility of targeting this protein class for treatment of selected cancers. A unique member of the RTK family, c-Met, also represents an intriguing target for cancer therapy that is yet to be explored in a clinical setting. The proto-oncogene, c-Met, encodes the high-affinity receptor for hepatocyte growth factor (HGF) or scatter factor (SF). c-Met and HGF are each required for normal mammalian development and have been shown to be particularly important in cell migration, morphogenic differentiation, and organization of three-dimensional tubular structures (e.g. renal tubular cells, gland formation, etc.) as well as cell growth and angiogenesis. Both c-Met and HGF have been shown to be deregulated in and to correlate with poor prognosis in a number of major human cancers. New data describing the constitutive phosphorylation of c-Met in a number of human tumors is presented here along with a variety of mechanisms by which c-Met can become activated, including mutation and gene amplification. In support of the clinical data implicating c-Met activation in the pathogenesis of human cancers, introduction of c-Met and HGF (or mutant c-Met) into cells conferred the properties of motility, invasiveness, and tumorgenicity to the transformed cells. Conversely, the inhibition of c-Met with a variety of receptor antagonists inhibited the motility, invasiveness, and tumorgenicity of human tumor cell lines. Consistent with this observation, small-molecule inhibitors of c-Met were developed that antagonized c-Met/HGF-dependent phenotypes and tumor growth in mouse models. This review will address the potential for development of c-Met inhibitors for treatment of human cancers with particular emphasis on recent findings with small-molecule inhibitors.     

Telomerase as a diagnostic and therapeutic target for cancer

Telomerase is a ribonucleoprotein enzyme responsible for the elongation of telomeres at the ends of chromosomes. It is widely expressed in most cancers, while absent from most normal somatic cells. Telomerase is partially responsible for the cellular immortalization that allows human cancers to progress indefinitely. Due to its widespread occurrence in cancer and its crucial role in the maintenance of the tumor, telomerase is an attractive target for cancer diagnosis and treatment.     

Telomerase as a diagnostic and therapeutic target for cancer

Telomerase is a ribonucleoprotein enzyme responsible for the elongation of telomeres at the ends of chromosomes. It is widely expressed in most cancers, while absent from most normal somatic cells. Telomerase is partially responsible for the cellular immortalization that allows human cancers to progress indefinitely. Due to its widespread occurrence in cancer and its crucial role in the maintenance of the tumor, telomerase is an attractive target for cancer diagnosis and treatment.     

VEGF as a therapeutic target in cancer

Tumors require nutrients and oxygen in order to grow, and new blood vessels, formed by the process of angiogenesis, provide these substrates. The key mediator of angiogenesis is vascular endothelial growth factor (VEGF), which is induced by many characteristics of tumors, most importantly hypoxia. Therefore, VEGF is an appealing target for anticancer therapeutics. In addition, VEGF is easy to access as it circulates in the blood and acts directly on endothelial cells. VEGF-mediated angiogenesis is rare in adult humans (except wound healing and female reproductive cycling), and so targeting the molecule should not affect other physiological processes. Tumor blood vessels, formed under the influence of VEGF, are disorganized, tortuous and leaky with high interstitial pressure, reducing access for chemotherapies. Inhibiting VEGF would reduce the vessel abnormality and increase the permeability of the tumor to chemotherapies. Several approaches to targeting VEGF have been investigated. The most common strategies have been receptor-targeted molecules and VEGF-targeting molecules. The disadvantage of receptor-targeted approaches is that the VEGF receptors also bind different members of the VEGF super-family and affect systems other than angiogenesis. The best-studied and most advanced approach to VEGF inhibition is the humanized monoclonal antibody bevacizumab (Avastin), which is the only anti-angiogenic agent approved for treatment of cancer.     

Validating survivin as a cancer therapeutic target

Acquisition of the ability to evade cellular suicide, or apoptosis, is one of the master switches that contributes to cellular transformation and, ultimately, to invasive cancer. Much has been learned about the molecular organization of apoptotic pathways and their regulators, but the identification and validation of translational targets for apoptosis-based cancer therapy has posed a great challenge. Survivin is an attractive candidate for cancer therapy, so what is its potential applicability in the clinic?     

Smoothened as a new therapeutic target for human osteosarcoma

Background  

The Hedgehog signaling pathway functions as an organizer in embryonic development. Recent studies have demonstrated constitutive activation of Hedgehog pathway in various types of malignancies. However, it remains unclear how Hedgehog pathway is involved in the pathogenesis of osteosarcoma. To explore the involvement of aberrant Hedgehog pathway in the pathogenesis of osteosarcoma, we investigated the expression and activation of Hedgehog pathway in osteosarcoma and examined the effect of SMOOTHENED (SMO) inhibition.     

Autophagy as a therapeutic target in cancer

Autophagy is a self-catabolic process that maintains intracellular homeostasis and prolongs cell survival under stress via lysosomal degradation of cytoplasmic constituents and recycling of amino acids and energy. Autophagy is intricately involved in many aspects of human health and disease, including cancer. Autophagy is a double-edged sword in tumorigenesis, acting both as a tumor suppressor and a protector of cancer cell survival, and elucidation of its exact role at different stages of cancer progression and in treatment responsiveness is a complex and challenging task. Better understanding of autophagy regulation and its impact on treatment outcome will potentially allow us to identify novel therapeutic targets in cancer. In this review, we summarize current knowledge on the regulation and dual function of autophagy in tumorigenesis, as well as ongoing efforts in modulating autophagy for cancer treatment and prevention. This is a very exciting and highly promising area of cancer research, as pharmacologic modulation of autophagy appears to augment the efficacy of currently available anticancer regimens and opens the way to the development of new combinatorial therapeutic strategies that will hopefully contribute to cancer eradication.     

The hedgehog pathway as a therapeutic target for treatment of breast cancer

The Hedgehog (Hh) signaling pathway plays a key role in a variety of processes, such as embryogenesis and maintenance of adult tissue homeostasis. It is also becoming increasingly clear that this pathway can have a crucial role in tumorigenesis. Most recently, the Hh signaling pathway has been implicated in the development and maintenance of breast cancer. Here we review Hh signaling, advances in small molecule and antibody-based inhibitors targeting the Hh pathway, and dysregulation of the Hh signaling pathway in breast cancer.     

The TGFß pathway as a therapeutic target in cancer

The TGFß pathway has recently emerged as a putative therapeutic target against cancer. However, TGFß has a complex and dual role in cancer. In normal epithelial cells and early tumours, TGFß acts as a tumour suppressor. In contrast, during tumour progression TGFß becomes an oncogenic factor inducing proliferation, angiogenesis, invasion and metastasis, as well as suppressing the anti-tumoral immune response. The role of TGFß in oncogenesis requires the precise understanding of the TGFß pathway in order to design optimal therapeutic approaches and select the patient population that may benefit from an anti-TGFß therapy. Here we review the rationale for evaluating TGFß signalling inhibitors as cancer therapeutics, and the progress made in the preclinical and clinical testing of anti-TGFß compounds.     

Apoptotic pathways as a therapeutic target for colorectal cancer treatment

Colorectal cancer is the second leading cause of death from cancer among adults. The disease begins as a benign adenomatous polyp, which develops into an advanced adenoma with high-grade dysplasia and then progresses to an invasive cancer. Appropriate apoptotic signaling is fundamentally important to preserve a healthy balance between cell death and cell survival and in maintaining genome integrity. Evasion of apoptotic pathway has been established as a prominent hallmark of several cancers. During colorectal cancer development, the balance between the rates of cell growth and apoptosis that maintains intestinal epithelial cell homeostasis gets progressively disturbed. Evidences are increasingly available to support the hypothesis that failure of apoptosis may be an important factor in the evolution of colorectal cancer and its poor response to chemotherapy and radiation. The other reason for targeting apoptotic pathway in the treatment of cancer is based on the observation that this process is deregulated in cancer cells but not in normal cells. As a result, colorectal cancer therapies designed to stimulate apoptosis in target cells would play a critical role in controlling its development and progression. A better understanding of the apoptotic signaling pathways, and the mechanisms by which cancer cells evade apoptotic death might lead to effective therapeutic strategies to inhibit cancer cell proliferation with minimal toxicity and high responses to chemotherapy. In this review, we analyzed the current understanding and future promises of apoptotic pathways as a therapeutic target in colorectal cancer treatment.     

Oxidative phosphorylation as a potential therapeutic target for cancer therapy

In contrast to prior belief, cancer cells require oxidative phosphorylation (OXPHOS) to strive, and exacerbated OXPHOS dependency frequently characterizes cancer stem cells, as well as primary or acquired resistance against chemotherapy or tyrosine kinase inhibitors. A growing arsenal of therapeutic agents is being designed to suppress the transfer of mitochondria from stromal to malignant cells, to interfere with mitochondrial biogenesis, to directly inhibit respiratory chain complexes, or to disrupt mitochondrial function in other ways. For the experimental treatment of cancers, OXPHOS inhibitors can be advantageously combined with tyrosine kinase inhibitors, as well as with other strategies to inhibit glycolysis, thereby causing a lethal energy crisis. Unfortunately, most of the preclinical data arguing in favor of OXPHOS inhibition have been obtained in xenograft models, in which human cancer cells are implanted in immunodeficient mice. Future studies on OXPHOS inhibitors should elaborate optimal treatment schedules and combination regimens that stimulate—or at least are compatible with—anticancer immune responses for long-term tumor control.     

HER2 as a novel therapeutic target for cervical cancer

Surgery and radiation are the current standard treatments for cervical cancer. However, there is no effective therapy for metastatic or recurrent cases, necessitating the identification of therapeutic targets. In order to create preclinical models for screening potential therapeutic targets, we established 14 patient-derived xenograft (PDX) models of cervical cancers using subrenal implantation methods. Serially passaged PDX tumors retained the histopathologic and genomic features of the original tumors. Among the 9 molecularly profiled cervical cancer patient samples, a HER2-amplified tumor was detected by array comparative genomic hybridization and targeted next-generation sequencing. We confirmed HER2 overexpression in the tumor and serially passaged PDX. Co-administration of trastuzumab and lapatinib in the HER2-overexpressed PDX significantly inhibited tumor growth compared to the control. Thus, we established histopathologically and genomically homologous PDX models of cervical cancer using subrenal implantation. Furthermore, we propose HER2 inhibitor-based therapy for HER2-amplified cervical cancer refractory to conventional therapy.     

Translation regulation as a therapeutic target in cancer

Protein synthesis is a vital cellular process that regulates growth and metabolism. It is controlled via signaling networks in response to environmental changes, including the presence of nutrients, mitogens, or starvation. The phosphorylation state of proteins involved in translation initiation is a limiting factor that regulates the formation or activity of translational complexes. In cancer cells, hyperactivated signaling pathways influence translation, allowing uncontrolled growth and survival. In addition, several components of translation initiation have been found to be mutated, posttranslationally modified, or differentially expressed, and some act as oncogenes in cancer cells. Translational alterations can increase the overall rate of protein synthesis as well as activate regulatory mechanisms leading to the translation of specific messenger RNAs for proteins that promote cancer progression and survival. Many recent studies investigating such mechanisms have produced ideas for therapeutic intervention. This review describes altered mechanisms of protein synthesis in human cancers and discusses therapeutic approaches based on the targeting of translation. Cancer Res; 72(16); 3891-900. ?2012 AACR.