Diane D. Nguyen

Application of vitamin D and derivatives in hematological malignancies.

The role of vitamin D in the inhibition of malignant cell proliferation in hematological malignancies is indicative of its future use in cancer therapy. An understanding of the biochemical mechanism by which vitamin D and its derivatives exert their effects will prove to be useful in the development of clinically applicable therapies involving vitamin D. While the use of vitamin D in clinical trials against acute myeloid leukemia and myelodysplastic syndrome has been met with few successes thus far, in vitro and in vivo studies as well as epidemiological correlations between vitamin D deficiency and cancer have implicated the great potential of the use of vitamin D derivatives in effective therapies against neoplastic diseases. For these reasons, a focus on current understanding of role of vitamin D and derivatives in hematologic malignancies is relevant and the goal for this review.

Mast cells and the liver aging process

It has now ascertained that the clinical manifestations of liver disease in the elderly population reflect both the cumulative effects of longevity on the liver and the generalized senescence of the organism ability to adjust to metabolic, infectious, and immunologic insults. Although liver tests are not significantly affected by age, the presentation of liver diseases such as viral hepatitis may be subtler in the elderly population than that of younger patients.Human immunosenescence is a situation in which the immune system, particularly T lymphocyte function, deteriorates with age, while innate immunity is negligibly affected and in some cases almost up-regulated.We here briefly review the relationships between the liver aging process and mast cells, the key effectors in a more complex range of innate immune responses than originally though.

The Role of Human Papilloma Virus (HPV) Infection in Non-Anogenital Cancer and the Promise of Immunotherapy: A Review

Over the past 30 years, human papilloma virus (HPV) has been shown to play a role in the development of various cancers. Most notably, HPV has been linked to malignant progression in neoplasms of the anogenital region. However, high-risk HPV has also been suggested to play a significant role in the development of cancers in other anatomic locations, such as the head and neck, lung, breast and bladder. In 2006, the first vaccine for HPV, Gardasil, was approved for the prevention of subtypes 6, 11, 16 and 18. A few years later, Cevarix was approved for the prevention of subtypes 16 and 18, the HPV subtypes most frequently implicated in malignant progression. Although increased awareness and vaccination could drastically decrease the incidence of HPV-positive cancers, these approaches do not benefit patients who have already contracted HPV and developed cancer as a result. For this reason, researchers need to continue developing treatment modalities, such as targeted immunotherapies, for HPV-positive lesions. Here, we review the potential evidence linking HPV infection with the development of non-anogenital cancers and the potential role of immunotherapy in the prevention and eradication of HPV infection and its oncogenic sequela.

Galectin-3 inhibition suppresses drug resistance, motility, invasion and angiogenic potential in ovarian cancer

OBJECTIVE Ovarian cancer is the most deadly gynecologic malignancy worldwide. Since the pathogenesis of ovarian cancer is incompletely understood, and there are no available screening techniques for early detection, most patients are diagnosed with advanced, incurable disease. In an effort to develop innovative and effective therapies for ovarian cancer, we tested the effectiveness of Galecti-3C in vitro. This is a truncated, dominant negative form of Galectin-3, which is thought to act by blocking endogenous Galectin-3. METHODS We produced a truncated, dominant-negative form of Galectin-3, namely Galetic-3C. Ovarian cancer cell lines and primary cells from ovarian cancer patients were treated with Galectin-3C, and growth, drug sensitivity, and angiogenesis were tested. RESULT We show, for the first time, that Galectin-3C significantly reduces the growth, motility, invasion, and angiogenic potential of cultured OC cell lines and primary cells established from OC patients. CONCLUSIONS Our findings indicate that Galectin-3C is a promising new compound for the treatment of ovarian cancer.

Anti-Galectin-3 Therapy: A New Chance for Multiple Myeloma and Ovarian Cancer?

Here we review the role of Galectins in the molecular pathogenesis of multiple myeloma and ovarian cancer, with a special focus on Glectin-3. Multiple myeloma is the second most common hematologic malignancy worldwide. Because the pathogenesis of multiple myeloma is still incompletely understood, there is no ultimately effective cure, and this cancer results fatal. Ovarian cancer is the most lethal gynecologic malignancy worldwide. Due to the lack of screening techniques for early detection, patients are mostly diagnosed with advanced disease, which results ultimately fatal. Multiple myeloma and ovarian cancer have different biologies, but they share a strong dependence on adhesion with extracellular matrix and other cells. Galectin-3 plays a key role in regulating such adhesive abilities of tumor cells. Here we discuss the outcomes and possible mechanism of action of a truncated, dominant negative form of Galectin-3, Galectin-3C, in these malignancies. Overall, we report that Galectin-3C is a promising new compound for effective adjuvant therapies in advanced, refractory multiple myeloma and ovarian cancer.

Cancer Testes Antigens in Breast Cancer: Biological Role, Regulation, and Therapeutic Applicability

Breast cancer remains one of the leading causes of death among women across the world. The last few decades have seen significant reduction in mortality owing to earlier detection and better adjuvant treatments that were developed based on clinical staging and morphological features. As these treatments have evolved, the heterogeneity of breast cancer poses a new challenge, since there is no standard gold-therapy suitable for all tumors of the mammary gland. Therefore, contemporary management and research efforts are directed toward specific prognostic and predictive molecular signatures that can guide targeted individualized therapy. The goal of ongoing research in this field is to identify specific molecular targets for developing novel therapeutic approaches. These targets can also serve to improve screening of breast cancer. This review focuses on the role of cancer testis antigens (CTAs) in breast carcinogenesis and explores the potential for development of targeted screening and therapeutic approaches. Normally found in the testes, these antigens are highly correlative with cancers of the breast, skin, and ovaries. These implications have been further corroborated through uncovering the interaction of CTAs with genes and proteins involved in tumor suppression and homeostasis like p53. There is some evidence that these genes can be targeted for early detection in addition to being candidates for cancer immunotherapy.

Cancer testis antigen Sperm Protein 17 as a new target for triple negative breast cancer immunotherapy

Breast carcinoma is a major health issue for millions of women. Current therapies have serious side effects, and are only partially effective in patients with metastatic tumors. Thus, the need for novel and less toxic therapies is urgent. Moreover, hormonal and antibody therapies effective in other subtypes are not effective in Triple Negative Breast Cancer (TNBC). Immunotherapeutic strategies directed against specific tumor-associated antigens (TAAs) and mediated by specific cytotoxic T lymphocytes (CTL) have been largely underexplored in this disease. Cancer-testis antigens (CTA) are a group of TAAs displaying the ideal characteristics of promising vaccine targets, i.e. strong immunogenicity and cancer specificity. The CTA, Sperm Protein 17 (SP17), has been found to be aberrantly expressed in different neoplasms, including ovarian and esophageal cancers, nervous system tumors and multiple myeloma, and has been suggested as a candidate target for immunotherapy. Here, we evaluated SP17 expression levels in breast cancer cell lines, invasive ductal breast carcinoma, including patients with TNBC, and adjacent non-neoplastic breast tissue, and determined whether SP17 was capable of generating SP17-specific cytotoxic T lymphocytes in vitro. We showed that SP17 is expressed in breast cancer cell lines and primary breast tumors and importantly in TNBC subtype, but not in adjacent non-tumoral breast tissue or unaffected tissues, except in male germinal cells. Furthermore, we detected specific anti-SP17 antibodies in patients’ sera and we generated SP17-specific, HLA class I-restricted, cytotoxic T lymphocytes capable of efficiently killing breast cancer cells.

The cancer-testis antigen, sperm protein 17, a new biomarker and immunological target in head and neck squamous cell carcinoma

Head and Neck Squamous Cell Carcinoma is a deadly and locally aggressive malignancy that frequently portends a poor prognosis. Since current treatment modalities including surgery, chemotherapy and radiation are heavily debilitating and often result in recurrence intense efforts have been put into the development of novel less toxic and more lasting treatment strategies. Recently, immunotherapy has been proposed as a promising alternative that could potentially meet these requirements. SP17 is a validated cancer-testis antigen in multiple myeloma, ovarian cancer and non-small cell lung cancer. We aim at studying SP17 expression in HNSCC and its immunogenicity as a possible future target for HNSCC therapeutic vaccines. SP17 expression was evaluated in tissue specimens of HNSCC patients and controls. Moreover, SP17 immunogenicity was studied by generating autologous dendritic cells in vitro from the peripheral blood mononucleated cells of HNSCC patients and testing their ability to induce SP17 specific cytotoxic lymphocytes capable of killing autologous tumor cells in vitro. SP17specific immune responses were also evaluated in HNSCC patients as circulating anti-SP17 autoantibodies. SP17 was expressed in HNSCC tissues of HNSCC patients. Autologous dendritic cells pulsed with SP17 antigen induced powerful SP17 MHC class-I restricted, perforin-dependent, cytotoxic T-cells capable of efficiently killing autologous tumor cells in vitro. SP17-specific autoantibodies were detectable in the serum of HNSCC patients irrespective of tumor site or TNM stage. In conclusion, SP17 is an ideal immunotherapeutic target for HNSCC and a potential serological biomarker of the disease.

Immunopathology of Specific Cancers in Males and Females and Immunotherapy of Prostate and Cervical Cancer

Cancer remains one of the most complex diseases affecting humans, and despite the impressive advances that have been made in molecular and cell biology, how cancer cells progress through carcinogenesis and acquire their metastatic ability is still widely debated. Prostate cancer emerges from multiple alterations that induce changes in expression patterns of genes and proteins that function in networks controlling critical molecular and cellular events. Based on the exponential aging of the population and the increasing life expectancy in industrialized Western countries, prostate cancer is becoming a disease of increasing significance. While the incidence of cervical cancer has declined significantly in the USA, ethnic disparities remain in terms of increased mortality and morbidity. Here, it is aimed to review the clinical experiences and results achieved with immunotherapy for treating prostate and cervical cancers, two of the most significant malignancies in human male and females, respectively.