Leonardo Mirandola

Anti-Notch treatment prevents multiple myeloma cells localization to the bone marrow via the chemokine system CXCR4/SDF-1.

Multiple myeloma (MM) is a deadly hematopoietic malignancy characterized by proliferation of malignant plasma cells in the bone marrow (BM) and bone disease. Interactions between myeloma and BM cells facilitate tumor progression and resistance to therapies. CXCR4 and its ligand Stromal cell-derived factor-1 (SDF-1) have a primary role in this process and are associated with poor prognosis. The Notch pathway is active in myeloma cells, resulting in increased proliferation, resistance to apoptosis and osteolytic activity. We hypothesized that the CXCR4/SDF-1 axis mediates the effects of Notch signals in myeloma cells. Here we show that Notch positively controls CXCR4/SDF-1 expression and functions in myeloma cell lines, and that forced CXCR4 activation partially rescues tumor cells from the outcomes of Notch inhibition. Additionally, we provide evidences that Notch blocking in vivo significantly reduces BM infiltration by human myeloma cells in mouse xenografts. This is the first evidence that a Notch-targeted approach effectively prevents MM cell migration, proliferation and resistance to apoptosis by reducing CXCR4 and SDF-1 levels.

Galectin-3C Inhibits Tumor Growth and Increases the Anticancer Activity of Bortezomib in a Murine Model of Human Multiple Myeloma

Galectin-3 is a human lectin involved in many cellular processes including differentiation, apoptosis, angiogenesis, neoplastic transformation, and metastasis. We evaluated galectin-3C, an N-terminally truncated form of galectin-3 that is thought to act as a dominant negative inhibitor, as a potential treatment for multiple myeloma (MM). Galectin-3 was expressed at varying levels by all 9 human MM cell lines tested. In vitro galectin-3C exhibited modest anti-proliferative effects on MM cells and inhibited chemotaxis and invasion of U266 MM cells induced by stromal cell-derived factor (SDF)-1α. Galectin-3C facilitated the anticancer activity of bortezomib, a proteasome inhibitor approved by the FDA for MM treatment. Galectin-3C and bortezomib also synergistically inhibited MM-induced angiogenesis activity in vitro. Delivery of galectin-3C intravenously via an osmotic pump in a subcutaneous U266 cell NOD/SCID mouse model of MM significantly inhibited tumor growth. The average tumor volume of bortezomib-treated animals was 19.6% and of galectin-3C treated animals was 13.5% of the average volume of the untreated controls at day 35. The maximal effect was obtained with the combination of galectin-3C with bortezomib that afforded a reduction of 94% in the mean tumor volume compared to the untreated controls at day 35. In conclusion, this is the first study to show that inhibition of galectin-3 is efficacious in a murine model of human MM. Our results demonstrated that galectin-3C alone was efficacious in a xenograft mouse model of human MM, and that it enhanced the anti-tumor activity of bortezomib in vitro and in vivo. These data provide the rationale for continued testing of galectin-3C towards initiation of clinical trials for treatment of MM.

Identification of AKAP-4 as a new cancer/testis antigen for detection and immunotherapy of prostate cancer†

Prostate cancer (PC) is the second most common cancer in older men, after skin cancer. PC is difficult to diagnose because the prostate‐specific antigen screening method is associated with many false positives. In addition there is a need to develop new and more effective treatments. Among presently available new treatments, immunotherapy is a promising approach. We investigated the expression of the cancer/testis antigen, AKAP‐4, in PC patients to evaluate the possibility of exploiting AKAP‐4 as a target for immunotherapy.

Cancer Testis Antigens: Novel Biomarkers and Targetable Proteins for Ovarian Cancer

Ovarian cancer is the fifth leading cause of cancer death in women and the leading cause from gynecological malignancies. Despite the recently improved outcomes of new chemotherapeutical agents in the therapy of ovarian cancer and the increased 5-year survival rate, the mortality of this malignancy disease remains unchanged. Ovarian cancer therapy is often correlated to the stage of the tumor, but the first step is usually surgical treatment. Afterward, various courses of chemotherapy and radiation are suggested. Obviously, the higher the developmental stage of the tumor, the less the probability is in eradicating it surgically, especially in relation to metastasis. It is clear that an early diagnosis of ovarian cancer is important for the survival of these patients. In order to identify ovarian cancer patients in the early stages, a number of studies are focusing on a particular class of antigens called cancer testis antigens. These antigens display high expression in tumors of different histology, but are normally restricted to the testis and have low or no expression in normal tissues. The testes are an immunologically-privileged site due to the presence of tight junctions between adjacent Sertoli cells that constitute the blood-testis barrier, which prevents auto-immune reactions. In the past few years, some of these antigens were demonstrated to be very promising for the early diagnosis and development of vaccines for ovarian cancer. This review aims to underline the most reliable cancer testis antigens under investigation at this moment.

Notch-directed microenvironment reprogramming in myeloma: a single path to multiple outcomes

Multiple myeloma is a deadly hematopoietic malignancy. Despite therapeutic advances such as autologous stem cell transplantation and novel chemotherapeutics, multiple myeloma remains incurable. Multiple myeloma cell localization in the bone marrow and the cross-talk with the bone niche trigger dramatic alterations in the bone marrow microenvironment critical for tumor progression, resistance to therapies and osteolytic bone destruction. It does not surprise that the molecular bases of such fatal interaction are under examination as source of novel potential pharmacological targets. Among these, the Notch family of receptors and ligands has gained growing interest in the recent years because of their early deregulation in multiple myeloma and their ability to affect multiple features of the disease, including tumor cell growth, drug resistance, angiogenesis and bone lesions. This review will explore the evidences of Notch deregulation in multiple myeloma, the state of the art of the currently known roles of its signaling in the fatal interaction between multiple myeloma cells, extracellular matrix and cells in the bone marrow stroma. Finally, we will present recent findings concerning the arguments for or against a therapy addressed to Notch signaling inhibition in the cure of multiple myeloma.

Cancer Testis Antigen Vaccination Affords Long-Term Protection in a Murine Model of Ovarian Cancer

Sperm protein (Sp17) is an attractive target for ovarian cancer (OC) vaccines because of its over-expression in primary as well as in metastatic lesions, at all stages of the disease. Our studies suggest that a Sp17-based vaccine can induce an enduring defense against OC development in C57BL/6 mice with ID8 cells, following prophylactic and therapeutic treatments. This is the first time that a mouse counterpart of a cancer testis antigen (Sp17) was shown to be expressed in an OC mouse model, and that vaccination against this antigen significantly controlled tumor growth. Our study shows that the CpG-adjuvated Sp17 vaccine overcomes the issue of immunologic tolerance, the major barrier to the development of effective immunotherapy for OC. Furthermore, this study provides a better understanding of OC biology by showing that Th-17 cells activation and contemporary immunosuppressive T-reg cells inhibition is required for vaccine efficacy. Taken together, these results indicate that prophylactic and therapeutic vaccinations can induce long-standing protection against OC and delay tumor growth, suggesting that this strategy may provide additional treatments of human OC and the prevention of disease onset in women with a family history of OC.

Notch-ing from T-cell to B-cell lymphoid malignancies.

Notch receptors are transmembrane proteins critically determining cell fate and maintenance of progenitor cells in many developmental systems. Notch signaling is involved in stem cell self-renewal and regulates the main functions of cell life at different levels of development: cell proliferation, differentiation and apoptosis. By virtue of its involvement in the regulation of cell physiology, it is not surprising that a deregulation of the Notch pathway leads to the development of different tumors. In this review, we critically discuss the latest findings concerning Notch roles in hematologic oncology, with a special focus on T-cell acute lymphoblastic leukemia and B-cell malignancies. We also describe the molecular mediators of Notch-driven oncogenic effects and the current pharmacological approaches targeting Notch signaling.

Aging, cancer, and cancer vaccines.

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.

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.

Chimeric Antigen Receptor Engineering: A Right Step in the Evolution of Adoptive Cellular Immunotherapy

Cancer immunotherapy comprises different therapeutic strategies that exploit the use of distinct components of the immune system, with the common goal of specifically targeting and eradicating neoplastic cells. These varied approaches include the use of specific monoclonal antibodies, checkpoint inhibitors, cytokines, therapeutic cancer vaccines and cellular anticancer strategies such as activated dendritic cell (DC) vaccines, tumor-infiltrating lymphocytes (TILs) and, more recently, genetically engineered T cells. Each one of these approaches has demonstrated promise, but their generalized success has been hindered by the paucity of specific tumor targets resulting in suboptimal tumor responses and unpredictable toxicities. This review will concentrate on recent advances on the use of engineered T cells for adoptive cellular immunotherapy (ACI) in cancer.