Current Cancer Therapy Reviews - Volume 2, Issue 4, 2006

The vast majority of nervous system neoplasms occur sporadically. However, most adult and pediatric tumors have a hereditary equivalent. These hereditary forms are an invaluable resource in the identification of genes that may be important for sporadic tumor development. In recent years there has been a tremendous increase in the understanding of the genetic basis of many familial cancer syndromes involving the central nervous system (CNS). Several key genes, important in the development of neoplastic disease, have been identified. These genes typically suppress the tumor phenotype (tumor-suppressor gene), maintain normal cellular function and homeostasis, and regulate cell growth and differentiation. Familial CNS tumors are mostly inherited as autosomal dominant traits and involve germline mutations. A somatic mutation inactivating the second allele subsequently results in neoplastic development. This article reviews several familial tumor syndromes involving the CNS including neurofibromatosis type-1, neurofibromatosis type-2, von Hippel-Lindau disease, tuberous sclerosis complex, Li-Fraumeni syndrome, Cowden's syndrome, Turcot's syndrome, Gorlin's syndrome, Fanconi anemia and multiple endocrine neoplasia. This review highlights their clinical manifestations, molecular genetics, pathophysiology and current treatment. The importance of these pathways for sporadic brain tumors, and the implications for future therapeutic and interventional therapies, are highlighted.

Penetration properties, studied in multicellular spheroids, of totally 23 radiolabeled or boronated substances are summarized. The spheroids were models for small non-vascularized metastases, and there is special emphasis on results obtained with a freeze-drying method. The substances were detected using autoradiography or neutron capture radiography. Certain substances, e.g. 5-FU, glucose, BSH and one antibody, penetrated efficiently, while others, e.g. vinblastine, an epidermal growth factor derivative, and two other types of antibodies only penetrated into the outer periphery of the spheroids in spite of long incubation time. The molecular weight of the substances did not relate well with the penetration properties. Instead, those substances that bound extensively had in most cases limited penetration. This was, for example, clearly shown for the drug Ara-C when applied to two different types of spheroids, one type giving low binding and good penetration and one giving extensive binding and less penetration. The penetration of an antibody and an EGF-derivative improved significantly when their binding sites were blocked. It is concluded that molecular weight is not a dominating determinant for penetration in the studied model, but that binding is. Such knowledge is valuable for the understanding of effects of chemotherapy, targeted radionuclide therapy and immunotherapy and for the development of new agents for such therapies.

The Ras/Raf signaling pathway mediates key signaling events involved in cell proliferation and angiogenesis and provides several targets for the development of therapeutic inhibitors. Raf kinases are a family of serine/threonine protein kinases that mediate many signaling events in response to growth factor signaling. Inappropriate activation of the MAP kinase pathway happens either through constitutive activation of growth factor receptors or through activating mutations in Ras and Raf. Such inappropriate activation can lead to growth factor independent proliferation, inactivation of tumor suppressor genes, angiogenesis, invasion, and metastasis. These activating mutations can also lead to suppression of apoptosis and resistance to chemotherapy. In essence, mutations of this pathway can lead to all of the hallmarks of cancer. Overactivation of the Ras/Raf/MEK/ERK pathway is common in most human malignancies. Therefore, all components of this cascade are attractive targets for anticancer therapies. In this context, certain Raf kinase inhibitors have been found to have significant anti-cancer activities and have been approved for clinical use recently. This review outlines the Raf family members structurally and functionally, and the strategies that are being developed to target them as anti-cancer agents.

Approximately 50% of new breast cancers occur in women aged 65 and older, and the incidence and prevalence of breast cancer among older women are expected to increase in the future. Moreover, in the past years, life expectancy has increased exceeding 10 years in patients aged 75 years. Aging is associated with a decline in the functional reserve of multiple organ systems, an increase in the prevalence of functional dependence, comorbidity and memory disorders, and a decline in economic resources and social support. All these aspects should be evaluated using some form of geriatric assessment, to rule out unsuspected conditions that may interfere with cancer treatment. Even if the course of breast cancer is more indolent in older than in younger women, up to 20% of women older than 70 years of age have aggressive hormone-receptor-poor tumors. Adequate surgical resection is the mainstay treatment for primary breast cancer even in older women. Lymph node dissection remains a major component of staging and local control, however owing to the sentinel lymph node technique, only women whose sentinel lymph node is invaded by the tumor do need full dissection. Radiation therapy reduces the recurrence rate for any category of tumors, including those occurring in older individuals. Adjuvant hormonal therapy should be recommended to women whose breast tumors contain hormone receptors, regardless of age, involvement of axillary nodes or tumor size. Tamoxifen is the most commonly used hormonal therapy, with data supporting one to five-year course of treatment in elderly patients. Recent results from trials comparing tamoxifen to aromatase inhibitors (anastrozole, letrozole and exemestane), given at different time points, have reported superior results of these drugs over tamoxifen in terms of disease-free survival but not of survival. Aromatase inhibitors can be considered for elderly women according to the degree of risk and biological features, and in those with contraindications to tamoxifen. As reported in the 2005 Early Breast Cancer Trialists Collaborative Group (EBCTCG) analysis, trials of adjuvant chemotherapy involved few women older than 70 years of age to be reliably informative as to whether it confers any survival benefit in this age group. For patients with hormone receptor negative tumors few specific published data are until now available, partly because these tumors represent a small subset in adjuvant studies in the elderly, and also because the distinction between ER poor and ER negative tumors is still a matter of controversy. It would be advisable to participate in currently open clinical trials that are addressing this issue. There is reluctance to prescribe systemic treatments due to the complexity of evaluation for these patients. Taking into account the limited amount of data and uncertainty regarding optimal treatment, individualized care on the basis of biologic characteristics, comorbidity, social support, functional status, and patient preferences should be considered. Trials of tailored adjuvant therapy should be a health care priority.

Oncology drug development is an increasingly complex effort involving multiple stakeholders on a global scale. This review summarizes the role of the United States Food and Drug Administration (USFDA) and its office of oncology drugs in the regulation of anticancer drug therapies. The regulatory history of FDA's mission will be summarized. The FDA's role from first-in-human dose finding studies to trials designed to evaluate efficacy, as well as post-marketing considerations will be outlined. During this entire process, the FDA is committed to productive interactions with all its stakeholders, including the public, the pharmaceutical industry, academia, other government agencies and patient advocacy groups.

Survivin is a unique member of the IAP family. It plays dual roles in inhibiting apoptosis and in regulating mitosis. Moreover, it is highly expressed in almost all types of human cancer but undetected in most normal adult tissues. High levels of survivin expression have been associated with cancer progression, drug resistance, poor prognosis and short patient survival. Therefore, survivin is regarded as a promising target for cancer treatment. Modulation of survivin expression may constitute an important, specific therapeutic approach. This review briefly summarizes the cellular signaling that regulates survivin transcription and evidence that upregulation of survivin expression promotes anticancer resistance and tumor progression. Recent studies demonstrate that the survivin promoter is strongly activated by several transcription factors including Sp/KLF family members and the β-catenin/TCF signaling pathway, which positively regulate cell proliferation and mediate cell survival, transformation, and tumorigenesis. Activation of survivin by these transcription factors is usually associated with mutation of tumor suppressor genes such as p53 and APC. Thus, this review will focus on the roles of transcription factors and their interactions with tumor suppressor genes in regulating survivin expression, and targeting of survivin promoter and transcriptional regulation, to assess whether that targeting might be a viable therapeutic approach against cancer.

Prostate cancer is an increasingly prevalent health problem among males, and the need for improved methods of treatment is great. In the 1940s estrogens were shown to be of benefit in prostate cancer, and their use continued for some 30 years, until the advent of LHRH agonists and similar drugs. At the time the mechanism of action of estrogens was thought to involve merely reduction in androgen levels, but new evidence, including expression of estrogen receptors by prostate epithelium and prostate cancer results showing a direct cytotoxic effect on prostate cancer, and preclinical data on inhibition of prostate cancer in intact female mice, suggests that estrogen exerts other effects on prostate cancer cells. Given that estrogens also decrease bone lysis caused by androgen suppression and may ameliorate cognitive side effects associated with low testosterone, estrogens show promise in treatment of androgen-independent prostate cancer. This review summarizes published reports of the effects on estrogens on prostate cancer in preclinical and clinical settings.

Physical exercise training has been shown to be an effective component of comprehensive rehabilitation for some cancer patients and survivors. The purpose of this paper is to review the potential role of exercise training in the clinical setting and examine methods to deliver these services in the clinical setting. Noting the limited direct research on implementation of clinical exercise programs in the cancer setting, we review the literature and propose guidelines for: 1) goals of the prescribed physical activity or exercise program; 2) medical and pre-exercise evaluations; 3) recommendations for exercise programming; 4) safety considerations; 5) barriers to physical activity and exercise training in cancer patients; 6) self-directed and community based exercise programs; and 7) the role of medical and exercise professionals.