Identifying cancer genes from cancer mutation profiles by cancer functions

It is of great importance to identify new cancer genes from the data of large scale genome screenings of gene mutations in cancers. Considering the alternations of some essential functions are indispensable for oncogenesis, we define them as cancer functions and select, as their approximations, a group of detailed functions in GO (Gene Ontology) highly enriched with known cancer genes. To evaluate the efficiency of using cancer functions as features to identify cancer genes, we define, in the screened genes, the known protein kinase cancer genes as gold standard positives and the other kinase genes as gold standard negatives. The results show that cancer associated functions are more efficient in identifying cancer genes than the selection pressure feature. Furthermore, combining cancer functions with the number of non-silent mutations can generate more reliable positive predictions. Finally, with precision 0.42, we suggest a list of 46 kinase genes as candidate cancer genes which are annotated to cancer functions and carry at least 3 non-silent mutations.     

Apoptosis pathways in cancer and cancer therapy

Activation of apoptosis pathways is a key mechanism by which cytotoxic drugs kill tumor cells. Also immunotherapy of tumors requires an apoptosis sensitive phenotype of target cells. Defects in apoptosis signalling contribute to resistance of tumors. Activation of apoptosis signalling following treatment with cytotoxic drugs has been shown to lead to activation of the mitochondrial (intrinsic) pathway of apoptosis. In addition, signalling through the death receptor (extrinsic) pathways, contributes to sensitivity of tumor cells towards cytotoxic treatment. Both pathways converge finally at the level of activation of caspases, the effector molecules in most forms of cell death. In addition to classical apoptosis, non-apoptotic modes of cell death have recently been identified. Mechanisms to overcome apoptosis resistance include direct targeting of antiapoptotic molecules expressed in tumors as well as re-sensitization of previously resistant tumor cells by re-expression of caspases and counteracting apoptotis inhibitory molecules such as Bcl-2 and molecules of the IAP family of endogenous caspase inhibitors. Molecular insights into regulation of apoptosis and defects in apoptosis signalling in tumor cells will provide novel approaches to define sensitivity or resistance of tumor cells towards antitumor therapy and provide new targets for rational therapeutic interventions for future therapeutic strategies.This work was presented at the first Cancer Immunology and Immunotherapy Summer School, 8–13 September 2003, Ionian Village, Bartholomeio, Peloponnese, Greece.     

Aging, cancer, and cancer vaccines

ABSTRACT: World population has experienced continuous growth since 1400 A.D. Current projections show a continued increase - but a steady decline in the population growth rate - with the number expected to reach between 8 and 10.5 billion people within 40 years. The elderly population is rapidly rising: in 1950 there were 205 million people aged 60 or older, while in 2000 there were 606 million. By 2050, the global population aged 60 or over is projected to expand by more than three times, reaching nearly 2 billion people 1. Most cancers are age-related diseases: in the US, 50% of all malignancies occur in people aged 65-95. 60% of all cancers are expected to be diagnosed in elderly patients by 2020 2. Further, cancer-related mortality increases with age: 70% of all malignancy-related deaths are registered in people aged 65 years or older 3. Here we introduce the microscopic aspects of aging, the pro-inflammatory phenotype of the elderly, and the changes related to immunosenescence. Then we deal with cancer disease and its development, the difficulty of treatment administration in the geriatric population, and the importance of a comprehensive geriatric assessment. Finally, we aim to analyze the complex interactions of aging with cancer and cancer vaccinology, and the importance of this last approach as a complementary therapy to different levels of prevention and treatment. Cancer vaccines, in fact, should at present be recommended in association to a stronger cancer prevention and conventional therapies (surgery, chemotherapy, radiation therapy), both for curative and palliative intent, in order to reduce morbidity and mortality associated to cancer progression.     

Re-purposing cancer therapeutics for breast cancer immunotherapy

After decades of work to develop immune-based therapies for cancer, the first drugs designed specifically to engage the host anti-tumor immune response for therapeutic benefit were recently approved for clinical use. Sipuleucel-T, a vaccine for advanced prostate cancer, and ipilimumab, a monoclonal antibody that mitigates the negative impact of cytotoxic T lymphocyte antigen-4 signaling on tumor immunity, provide a modest clinical benefit in some patients. The arrival of these drugs in the clinic is a significant advance that we can capitalize on for even better clinical outcomes. The strategic and scientifically rational integration of vaccines and other direct immunomodulators with standard cancer therapeutics should lead to therapeutic synergy and high rates of tumor rejection. This review focuses on the use of cyclophosphamide, doxorubicin, and HER-2-specific monoclonal antibodies to dissect mechanisms of immune tolerance relevant to breast cancer patients and illustrates how appropriate preclinical models can powerfully inform clinical translation. The immune-modulating activity of targeted, pathway-specific, small molecule therapeutics is also discussed. Fully understanding how cancer drugs impact the immune system should lead to the ultimate personalized cancer medicine: effective combinatorial immunotherapy strategies that simultaneously target signaling pathways essential for tumor growth and progression, and systematically break multiple, distinct immune tolerance pathways to maximize tumor rejection and effect cure.     

Targeting pancreatic cancer stem cells for cancer therapy

Pancreatic cancer (PC) is the fourth most frequent cause of cancer death in the United States. Emerging evidence suggests that pancreatic cancer stem cells (CSCs) play a crucial role in the development and progression of PC. Recently, there is increasing evidence showing that chemopreventive agents commonly known as nutraceuticals could target and eliminate CSCs that have been proposed as the root of the tumor progression, which could be partly due to attenuating cell signaling pathways involved in CSCs. Therefore, targeting pancreatic CSCs by nutraceuticals for the prevention of tumor progression and treatment of PC may lead to the development of novel strategy for achieving better treatment outcome of PC patients. In this review article, we will summarize the most recent advances in the pancreatic CSC field, with particular emphasis on nutraceuticals that target CSCs, for fighting this deadly disease.     

Endometrial cancer

Endometrial cancer is the most common gynaecological malignancy in the developed world. The majority of cases can be divided into two broad categories based on clinico-pathological and molecular characteristics; Type I oestrogen-dependent with endometrioid morphology and Type II non-oestrogen-dependent with serous papillary or clear cell morphology. As has been described for other malignancies, such as colorectal carcinoma, the transition from normal endometrium to carcinoma is thought to involve a stepwise accumulation of alterations in cellular regulatory pathways leading to dysfunctional cell growth. This article reviews the current knowledge of the molecular changes commonly associated with endometrial cancer and presents possible progression models.     

Profiling cancer

In the past couple of years, several very exciting studies have demonstrated the enormous power of gene-expression profiling for cancer classification and prediction of patient survival. In addition to promising a more accurate classification of cancer and therefore better treatment of patients, gene-expression profiling can result in the identification of novel potential targets for cancer therapy and a better understanding of the molecular mechanisms leading to cancer.     

Emerging roles for cancer registries in cancer control

Cancer registries are a vital part of the national cancer effort to cut United States cancer mortality rates in half by the year 2000. Registries provide the data to focus programs and monitor progress. Success in meeting the year 2000 goal will require aggressive attention to the opportunities for prevention, early detection, treatment, and applied cancer control research, all of which complement the current emphasis on basic research.