Local tumor control and survival: clinical evidence and tumor biologic basis

Clinical and tumor biologic evidence indicates that local tumor recurrence is associated with a higher rate of distant metastases and adverse effects on patient survival. The findings discussed in this article are based on results from breast, prostate, and lung carcinoma, all tumors with high metastatic potential for which local tumor control was thought to be relatively unimportant. The fact that local tumor recurrence is associated with tumor progression and significant increases in distant metastases has important consequences in the relative emphasis on and the sequencing of locoregional and systemic therapies in the future.     

In situ gene therapy for prostate cancer.

The natural history of prostate cancer presents a dilemma for those interested in developing effective treatment for the disease. When the disease is localized (and therefore potentially curable by localized therapies), it is often of uncertain biological potential and in many cases will not progress to clinical significance. However, both experimental and clinical studies indicate that prostate cancer can metastasize early and/or from relatively small foci of prostate cancer within the gland and is often systemic at the time of diagnosis. Unfortunately, there are no curative therapies for metastatic prostate cancer. In general, currently used therapies with the potential to be curative involve a single cytoablative modality (radical prostatectomy and irradiation therapy) and are directed exclusively at the malignant cells within the prostate gland. At present the widespread use of these treatments alone has not resulted in substantial reduction in mortality from the prostate cancer. Gene therapy used alone or as an adjuvant approach could, at least conceptually, provide a rational solution for the prostate cancer dilemma. With gene therapy, it may be possible to treat localized and systemic disease effectively and simultaneously. Indeed, in situ gene therapy protocols in which viral vectors are used to transduce specific genes that generate cytotoxic activity and/or systemic immunity to the cancer offer hope for significantly reducing the mortality from this disease. This commentary discusses early studies specifically aimed toward developing in situ-based gene therapies that can generate cytotoxic activities in localized prostate cancers and/or the generation of an immune response in the primary tumor that would affect systemic disease.     

Gene therpay for prostate cancer

Prostate cancer is the most common noncutaneous cancer in man. When confined to the prostate it can be cured by radical prostatectomy or irradiation therapy. However, there are no curative therapies for locally advanced, recurrent or metastatic disease. Prostate cancer gene therapy has recently transitioned from preclinical studies to clinical trials with the goal of developing novel treatments for prostate cancer. The greatest challenge in treating advanced prostate cancer is therapeutic access to and the elimination of metastases. This review details two aspects of prostate cancer gene therapy, the types of delivery systems under development and specific categories of therapeutic genes available with an emphasis on the mechanism of action of specific gene therapy strategies.     

Gene therapy for prostate cancer

Prostate cancer is the most common noncutaneous cancer in man. When confined to the prostate it can be cured by radical prostatectomy or irradiation therapy. However, there are no curative therapies for locally advanced, recurrent or metastatic disease. Prostate cancer gene therapy has recently transition from preclinical studies to clinical trials with the goal of developing novel treatments for prostate cancer. The greatest challenge in treating advanced prostate cancer is therapeutic access to and the elimination of metastases. This review details two aspects of prostate cancer gene therapy, the types of delivery systems under development and specific categories of therapeutic genes available with an emphasis on the mechanism of action of specific gene therapy strategies.     

Pathogenesis and treatment of prostate cancer bone metastases: targeting the lethal phenotype.

Traditionally, prostate cancer treatment, as well as all cancer treatment, has been designed to target the tumor cell directly via various hormonal and chemotherapeutic agents. Recently, the realization that cancer cells exist in complex microenvironments that are essential for the tumorigenic and metastatic potential of the cancer cells is starting the redefine the paradigm for cancer therapy. The propensity of prostate cancer cells to metastasize to bone is leading to the design of novel therapies targeting both the cancer cell as well as the bone microenvironment. Tumor cells in the bone interact with the extracellular matrix, stromal cells, osteoblasts, osteoclasts, and endothelial cells to promote tumor-cell survival and proliferation leading to a lethal phenotype that includes increased morbidity and mortality for patients with advanced prostate cancer. Several strategies are being developed that target these complex tumor cell-microenvironment interactions and target the signal transduction pathways of other cells important to the development of metastases, including the osteoclasts, osteoblasts, and endothelial cells of the bone microenvironment. Current and new therapies in metastatic prostate cancer will comprise a multitargeted approach aimed at both the tumor cell and the tumor microenvironment. Here, we review the current therapeutic strategies for targeting the prostate cancer-bone microenvironment and several single- and multiagent targeted approaches to the treatment of advanced prostate cancer that are under development.     

Current role of gene therapy in head and neck cancer.

Our increasing knowledge of cancer molecular biology has led to the development of new genetic therapies for the treatment of cancer. Such therapies are advantageous in that they can selectively target tumour tissue leaving normal tissue relatively unaffected. In squamous cell cancer of the head and neck, such therapies may be beneficial in the treatment of loco-regional recurrence, minimal residual disease and in the treatment of distant metastatic disease. This article describes the principles of cancer gene therapy reviews some early clinical trials of gene therapy in head and neck cancer.     

Local treatment of metastatic cancer--killing the seed or disturbing the soil?

The fact that local therapy of the primary tumor is futile in the presence of metastatic disease is almost considered axiomatic among oncologists. However, this perception is now being challenged by new laboratory and clinical data. Results from animal models have demonstrated that some primary tumors release factors that enter the circulation which, by mobilizing cells from bone marrow, render distant organs more receptive to metastasis. Clinical observations in renal, breast, and prostate cancer are all consistent with the hypothesis that treatment directed against the primary tumor might retard progression of existing metastases. This hypothesis is amenable to testing by randomized trials of local therapy to the primary site in patients with metastatic cancer.     

Androgen deprivation therapy sensitizes prostate cancer cells to T-cell killing through androgen receptor dependent modulation of the apoptotic pathway

Despite recent advances in diagnosis and management, prostrate cancer remains the second most common cause of death from cancer in American men, after lung cancer. Failure of chemotherapies and hormone-deprivation therapies is the major cause of death in patients with castration-resistant prostate cancer (CRPC). Currently, the androgen inhibitors enzalutamide and abiraterone are approved for treatment of metastatic CRPC. Here we show for the first time that both enzalutamide and abiraterone render prostate tumor cells more sensitive to T cell-mediated lysis through immunogenic modulation, and that these immunomodulatory activities are androgen receptor (AR)-dependent. In studies reported here, the NAIP gene was significantly down-regulated in human prostate tumor cells treated in vitro and in vivo with enzalutamide. Functional analysis revealed that NAIP played a critical role in inducing CTL sensitivity. Amplification of AR is a major mechanism of resistance to androgen-deprivation therapy (ADT). Here, we show that enzalutamide enhances sensitivity to immune-mediated killing of prostate tumor cells that overexpress AR. The immunomodulatory properties of enzalutamide and abiraterone provide a rationale for their use in combination with immunotherapeutic agents in CRPC, especially for patients with minimal response to enzalutamide or abiraterone alone, or for patients who have developed resistance to ADT.     

Drug development in prostate cancer

Despite strategies aimed at early detection and treatment, prostate cancer remains a leading cause of morbidity and mortality among males. Current therapies have limited impact on the natural history of metastatic hormone-refractory prostate cancer (HRPC). With an improved understanding of tumor biology, including apoptosis, differentiation, cell cycling and signaling, and angiogenesis, many potential new targets for therapy have been unveiled. Modulation of these processes may result in cytotoxic or cytostatic effects. The evaluation of therapies based on manipulation of these targets may not be adequately addressed by current study designs and traditional parameters of efficacy. Examples of agents currently in clinical trials that illustrate some of the challenges presented to clinical investigators include monoterpenes such as perillyl alcohol (POH), vitamin D analogs, flavones such as flavopiridol, and angiogenesis inhibitors. Agents such as these are aimed at unique cellular targets and will require novel approaches to determine their clinical utility. Unfortunately, in the United States, only a small proportion of cancer patients, including prostate cancer patients, are enrolled in clinical trials. We must do better to efficiently assess promising new treatment approaches and improve outcome for our patients.     

Adenovirus-mediated herpes simplex virus thymidine kinase gene and ganciclovir therapy leads to systemic activity against spontaneous and induced metastasis in an orthotopic mouse model of prostate cancer

It is critical to develop new therapies, such as gene therapy, which can impact on both local and metastatic prostate cancer progression. We have developed an orthotopic mouse model of metastatic prostate cancer using a cell line (RM-1) derived from the mouse prostate reconstitution (MPR) model system. This mouse model closely simulates the anatomical and biological milieu of the prostate and allows for realistic testing of experimental gene therapy protocols. Adenovirus (ADV)-mediated transduction of the herpes simplex virus thymidine kinase (HSV-tk) gene in conjunction with ganciclovir (GCV) in this model led to significant suppression of growth and of spontaneous metastasis at 14 days post-tumor inoculation. Longer-term studies produced a significant survival advantage and a continued suppression of metastatic activity for treatment animals despite regrowth of the primary tumor. Challenge by injection of tumor cells into the tail vein following excision of treated and control s.c. primary tumors resulted in 40% reduction in lung colonization in the treatment group, indicating the possible production of systemic anti-metastatic activity following a single in situ treatment with ADV/HSV-tk + GCV in this model system. Int. J. Cancer, 70:183–187, 1997. © 1997 Wiley-Liss, Inc.     

Apolipoprotein E expression in localized prostate cancers

Although prostate cancer has become the most common solid tumor diagnosed in men and the second leading cause of death due to malignancy, the progression of the disease is still somewhat unpredictable, until it becomes locally advanced or metastatic. The clinical problem to distinguish between dormant and progressive cancers is essential to patient care, as surgical and medical therapies have significant risk of morbidity and disability. Multiple gene expression in prostate cancer was surveyed by differential display cloning between the undifferentiated hormone refractory human prostate cancer cell line PC-3 (highly tumorigenic in nude mice) the hormone responsive LNCaP cell line (weakly tumorigenic in nude mice), and the poorly differentiated DU-145 cell line (moderately tumorigenic). ApoE mRNA was found to be highly expressed only in PC-3 cell-line. We further examined its protein expression by immunohistochemistry in 20 prostatectomy specimens and an association between Gleason score for each sample and ApoE expression was determined. ApoE expression correlates directly with the Gleason score in tissue sections, hormone independence as well as local and distant invasiveness. Prostatic intraepithelial neoplasias (PINs) adjacent to clinically manifested cancer were positive whereas more distant PINs were negative for ApoE. ApoE may represent a marker of more aggressive cells in human prostate cancers.     

Progress in active specific immunotherapy of prostate cancer

Treatments available for metastatic prostate cancer have failed to demonstrate significant curative potential. Current efforts are now directed towards developments of novel strategies for the treatment of metastatic prostate cancer. Cancer immunotherapeutic strategies utilize patient immune system components to kill cancer cells. This review discusses progress in active specific immunotherapeutic approaches as potential alternative methods in the treatment of metastatic prostate cancer. Various methods of augmenting the immune response against prostate cancer are discussed including systemic cytokine adjuvant therapy, cytokine gene transduced tumor vaccines, non-antigen specific immunization, DNA and peptide vaccines plus adjuvants, as well as dendritic cell-based cancer vaccines.     

Expanding the therapeutic index of radiation therapy by combining in situ gene therapy in the treatment of prostate cancer

The advances in radiotherapy (3D-CRT, IMRT) have enabled high doses of radiation to be delivered with the least possible associated toxicity. However, the persistence of cancer (local recurrence after radiotherapy) despite these increased doses as well as distant failure suggesting the existence of micro-metastases, especially in the case of higher risk disease, have underscored the need for continued improvement in treatment strategies to manage local and micro-metastatic disease as definitively as possible. This has prompted the idea that an increase in the therapeutic index of radiotherapy might be achieved by combining it with in situ gene therapy. The goal of these combinatorial therapies is to maximize the selective pressure against cancer cell growth while minimizing treatment-associated toxicity. Major efforts utilizing different gene therapy strategies have been employed in conjunction with radiotherapy. We reviewed our and other published clinical trials utilizing this combined radio-genetherapy approach including their associated pre-clinical in vitro and in vivo models. The use of in situ gene therapy as an adjuvant to radiation therapy dramatically reduced cell viability in vitro and tumor growth in vivo. No significant worsening of the toxicities normally observed in single-modality approaches were identified in Phase I/II clinical studies. Enhancement of both local and systemic T-cell activation was noted with this combined approach suggesting anti-tumor immunity. Early clinical outcome including biochemical and biopsy data was very promising. These results demonstrate the increased therapeutic efficacy achieved by combining in situ gene therapy with radiotherapy in the management of local prostate cancer. The combined approach maximizes tumor control, both local-regional and systemic through radio-genetherapy induced cytotoxicity and anti-tumor immunity.     

Metastatic cancer cells with macrophage properties: evidence from a new murine tumor model

Metastasis is the process by which cancer cells disseminate from the primary neoplasm and invade surrounding tissue and distant organs, and is the primary cause of morbidity and mortality for cancer patients. Most conventional cancer therapies are ineffective in managing tumor metastasis. This has been due in large part to the absence of in vivo metastatic models that represent the full spectrum of metastatic disease. Here we identify 3 new spontaneously arising tumors in the inbred VM mouse strain, which has a relatively high incidence of CNS tumors. Two of the tumors (VM-M2 and VM-M3) reliably expressed all of the major biological processes of metastasis to include local invasion, intravasation, immune system survival, extravasation and secondary tumor formation involving liver, kidney, spleen, lung and brain. Metastasis was assessed through visual organ inspection, histology, immunohistochemistry and bioluminescence imaging. The metastatic VM tumor cells also expressed multiple properties of macrophages including morphological appearance, surface adhesion, phagocytosis, total lipid composition (glycosphingolipids and phospholipids) and gene expression (CD11b, Iba1, F4/80, CD68, CD45 and CXCR4). The third tumor (VM-NM1) grew rapidly and expressed properties of neural stem/progenitor cells, but was neither invasive nor metastatic. Our data indicate that spontaneous brain tumors can arise from different cell types in VM mice and that metastatic cancer can represent a disease of macrophage-like cells similar to those described in several human metastatic cancers. The new VM tumor model will be useful for defining the biological processes of cancer metastasis and for evaluating potential therapies for tumor management.     

Advances in imaging in the postoperative patient with a rising prostate-specific antigen level

Imaging prostate cancer continues to represent a clinical challenge for both primary and recurrent disease. In the evaluation of the persistent/recurrent/metastatic prostate cancer, knowledge of cancer location (local v distant), size, and extent are essential in order to design a treatment, tailored to each patient's needs. There are evidence-based guidelines for the use of imaging in assessing the presence of distant spread of prostate cancer. Radionuclide bone scans and computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography (PET) supplement clinical and biochemical evaluations (prostate-specific antigen [PSA]) for suspected metastatic disease to bones and lymph nodes. There is no consensus about the use of imaging in the evaluation of local tumor recurrence. The use of ultrasound has been limited to biopsy guidance of the prostatic bed, or percutaneous biopsy of enlarged lymph nodes detected on CT or MRI. The use of MRI is evolving. Recent studies indicate that the use of MRI provides valuable information in the evaluation of local tumor recurrence, and nodal and bony metastases. In a patient post-radiation therapy, the method of combining MRI anatomic information with MR spectroscopic metabolic information is evolving. Another modality offering information about anatomy and metabolism of the local disease is PET/CT. The value of PET/CT at present is controversial, but new studies exploring the role of PET/CT in aggressive prostate cancer are promising.     

The Chinese medicinal herbal formula ZYD88 inhibits cell growth and promotes cell apoptosis in prostatic tumor cells

Prostate cancer is a leading cause of cancer death in American males. Currently, there is no curative therapy available once prostate cancer has metastasized. A major systemic therapy for metastatic prostate cancer is anti-androgen therapy. Unfortunately this therapy is only palliative and rarely curative, and eventually the tumor cells develop resistance to further hormone manipulation. It is therefore imperative to develop alternative effective therapies. In the present study, the effect of a Chinese herbal formula, ZYD88, on regulation of cell growth and cell apoptosis was examined in prostatic tumor cells. ZYD88 decreased cell viability of multiple prostatic tumor cell lines, DU-145, PC-3, MDA-PCa 2b and LNCaP in a time- and dose-dependent manner. It also produced a rapid and dose-dependent increase in caspase 3 activity in LNCaP and PC-3 cells, and induced DNA fragmentation in LNCaP cells, indicating cell apoptosis. In cotransfection assays, ZYD88 inhibited androgen-induced prostate specific antigen (PSA) gene promoter activity, and induced estrogen-target gene promoter activity. These data suggest that ZYD88 is a potential agent for prostate cancer therapy, and deserves further study.     

New systemic treatment options for metastatic renal‐cell carcinoma in the era of targeted therapies

Advances in understanding the biology and genetics of renal‐cell carcinomas have led to the development of novel targeted therapies for the treatment of metastatic renal‐cell cancer. Previously the systemic approaches were limited to cytokine therapies that were modest in their clinical benefits and at the expense of significant toxicities. Investigational treatments with allogeneic bone marrow transplantation were equally toxic and resulted in significant morbidity and mortality. The development of targeted therapy has revolutionized the treatment of metastatic renal‐cell cancer with more meaningful outcomes. This review aims to provide a detailed discussion of the clinical benefits of targeted therapies such as sunitinib, sorafenib, temsirolimus, everolimus, bevacizumab, and some of the newer agents in clinical trial development. The efficacy of these compounds in terms of response, survival and clinical benefit are explored as well as their toxicities. The role of surgery in metastatic renal‐cell carcinoma is reviewed in the context of cytoreductive therapy and resection of solitary and oligometastatic disease. Ongoing studies in the adjuvant setting following curative resection are also reviewed. The availability of targeted therapies has led to their rapid adoption as frontline therapy over traditional cytokine therapy, thus bringing more optimistic and hopeful therapeutic options in a condition where historically, systemic treatments have been relatively unsatisfactory and disappointing.     

Rat sodium iodide symporter for radioiodide therapy of cancer.

Design and development of new approaches for targeted radiotherapy of cancer and improvement of therapeutic index by more local radiation therapy are very important issues. Adenovirus-mediated delivery of the sodium iodide symporter (NIS) gene to cancer cells is a powerful technique to concentrate lethal radiation in tumor cells and eradicate tumors with increased therapeutic index. A replication-defective adenoviral vector expressing the rat NIS gene (Ad-rNIS) was used for in vitro gene delivery and into human prostate cancer xenografts to study antitumor effect. Robust function of the rat symporter was detected in DU145, T47D, and HCT-15 human cancer cell lines transduced with Ad-rNIS. All three cancer cell lines successfully transferred functionally active rat symporter to the plasma membrane, resulting in very high levels of iodine-125 accumulation. Three-dimensional multicellular tumor spheroids derived from DU145 human prostate cancer cells were transduced with Ad-rNIS and incubated with (131)I for 24 hours. After treatment, spheroids rapidly decreased in size and disappeared within 10 days. In vivo data revealed an inhibition of tumor growth in athymic nude mice after intratumoral Ad-rNIS injection followed by (131)I administration. Eighty-eight percent of experimental mice survived >30 days, whereas control groups had only 18% survival >30 days. This is the first report that demonstrates the rat NIS gene can effectively induce growth arrest of human tumor xenografts after in vivo adenoviral gene delivery and (131)I administration. The data confirm our hypothesis that the rat NIS gene is an attractive suicide gene candidate for cancer treatment.     

Metastasis-related Genes in Prostate Cancer: The Role of Caveolin-1

Prostate cancer continues to be a significant cause of death in U.S. men despite screening of asymptomatic men and extensive treatment with potentially curative therapies, predominantly radical prostatectomy and irradiation therapy. The reason for the persistent mortality resides in part in the presence of occult metastases at the time of treatment. Currently there are no curative therapies for metastatic prostate cancer. To better understand the metastatic phenotype in prostate cancer, we developed a strategy to compare and isolate mRNAs that are expressed differentially in cell lines derived from primary versus metastatic mouse prostate cancer using differential display-PCR. This strategy has proven to be successful and multiple gene sequences associated with metastasis in this model are being investigated. One of the genes isolated by this method was caveolin-1. Caveolin-1 was found to be overexpressed not only in metastatic mouse prostate cancer, but also human metastatic disease. Recent studies have indicated that suppression of caveolin expression induces androgen sensitivity in high-caveolin, androgen-insensitive mouse prostate cancer cells derived from metastases. Overexpression of caveolin leads to androgen insensitivity in low-caveolin, androgen-sensitive mouse prostate cancer cells. Caveolin-1, therefore, is a metastasis-related gene and a candidate gene for hormone-resistant prostate cancer in man.     

Chitosan nanoparticle-mediated delivery of miRNA-34a decreases prostate tumor growth in the bone and its expression induces non-canonical autophagy

While several new therapies are FDA-approved for bone-metastatic prostate cancer (PCa), patient survival has only improved marginally. Here, we report that chitosan nanoparticle-mediated delivery of miR-34a, a tumor suppressive microRNA that downregulates multiple gene products involved in PCa progression and metastasis, inhibited prostate tumor growth and preserved bone integrity in a xenograft model representative of established PCa bone metastasis. Expression of miR-34a induced apoptosis in PCa cells, and, in accord with downregulation of targets associated with PCa growth, including MET and Axl and c-Myc, also induced a form of non-canonical autophagy that is independent of Beclin-1, ATG4, ATG5 and ATG7. MiR-34a-induced autophagy is anti-proliferative in prostate cancer cells, as blocking apoptosis still resulted in growth inhibition of tumor cells. Thus, combined effects of autophagy and apoptosis are responsible for miR-34a-mediated prostate tumor growth inhibition, and have translational impact, as this non-canonical form of autophagy is tumor inhibitory. Together, these results provide a new understanding of the biological effects of miR-34a and highlight the clinical potential for miR-34a delivery as a treatment for bone metastatic prostate cancer.