Treatment for solid tumor malignancies, which constitute the majority of human cancers, is still dominated by surgery and radiotherapies. This is especially true for many localized solid tumors, ...which are often curable with these treatments. However, metastatic cancers are beyond the reach of these therapies, and many localized cancers that are initially treated with surgery and radiation will recur and metastasize. Thus, for over 60years there has been a concerted effort to develop effective drug treatments for metastatic cancers. Combination therapies are an increasingly important part of the anti-cancer drug armamentarium. In the case of cytotoxic chemotherapy, multi-drug regimens rapidly became the norm, as the earliest single agents were relatively ineffective. In contrast to chemotherapy, where combination therapies were required in order to achieve treatment efficacy, for both hormonal and targeted therapies the impetus to move toward the use of combination therapies is to prevent or reverse the development of treatment resistance. In addition, emerging evidence suggests that combination therapy may also improve cancer treatment by neutralizing an emerging treatment side effect termed therapy-induced metastasis, which accompanies some effective single agent therapies. Finally, although gene therapy is still far from use in the clinic, we propose that combination therapies may enhance its effectiveness.
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The incidence of renal cell carcinoma (RCC) is increasing worldwide with an approximate 20% mortality rate. The challenge in RCC is the therapy-resistance. Cancer resistance to treatment employs ...multiple mechanisms due to cancer heterogeneity with multiple genetic and epigenetic alterations. These changes include aberrant overexpression of (1) anticancer cell death proteins (e.g., survivin/BIRC5), (2) DNA repair regulators (e.g., ERCC6) and (3) efflux pump proteins (e.g., ABCG2/BCRP); mutations and/or deregulation of key (4) oncogenes (e.g., MDM2, KRAS) and/or (5) tumor suppressor genes (e.g., TP5/p53); and (6) deregulation of redox-sensitive regulators (e.g., HIF, NRF2). Foci of tumor cells that have these genetic alterations and/or deregulation possess survival advantages and are selected for survival during treatment. We will review the significance of survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, TP5/p53, KRAS and AKT in treatment resistance as the potential therapeutic biomarkers and/or targets in RCC in parallel with our analized RCC-relevant TCGA genetic results from each of these gene/protein molecules. We then present our data to show the anticancer drug FL118 modulation of these protein targets and RCC cell/tumor growth. Finally, we include additional data to show a promising FL118 analogue (FL496) for treating the specialized type 2 papillary RCC.
Understanding the mechanism of lymph node metastasis, a poor prognostic sign for prostate cancer, and the further dissemination of the disease is important to develop novel treatment strategies. ...Recent studies have reported that C‐C chemokine receptor 7 (CCR7), whose ligand is CCL21, is abundantly expressed in lymph node metastasis and promotes cancer progression. Tumor necrosis factor‐α (TNF‐α) is chronically produced at low levels within the tumor microenvironment. The aim of this study was to determine whether TNF‐α promotes prostate cancer dissemination from metastatic lymph nodes through activation of the CCL21/CCR7 axis. First, human prostate cancer cells were determined to express both TNF‐α and CCR7. Second, low concentrations of TNF‐α were confirmed to induce CCR7 in prostate cancer cells through phosphorylation of ERK. Finally, CCL21 was found to promote the migration of prostate cancer cells through phosphorylation of the protein kinase p38. Our results suggest that TNF‐α leads to the induction of CCR7 expression and that the CCL21/CCR7 axis might increase the metastatic potential of prostate cancer cells in lymph node metastasis.
TNF‐α acts as a regulator of increased prostate cancer cell migration via upregulation of CCR7. Targeting TNF‐α and ultimately the CCL21/CCR7 axis my be a novel therapeutic strategy in prostate cancer.
Autoimmune (AI) diseases can affect many organs; however, the prostate has not been considered to be a primary target of these systemic inflammatory processes. Here, we utilize medical record data, ...patient samples, and in vivo models to evaluate the impact of inflammation, as seen in AI diseases, on prostate tissue. Human and mouse tissues are used to examine whether systemic targeting of inflammation limits prostatic inflammation and hyperplasia. Evaluation of 112,152 medical records indicates that benign prostatic hyperplasia (BPH) prevalence is significantly higher among patients with AI diseases. Furthermore, treating these patients with tumor necrosis factor (TNF)-antagonists significantly decreases BPH incidence. Single-cell RNA-seq and in vitro assays suggest that macrophage-derived TNF stimulates BPH-derived fibroblast proliferation. TNF blockade significantly reduces epithelial hyperplasia, NFκB activation, and macrophage-mediated inflammation within prostate tissues. Together, these studies show that patients with AI diseases have a heightened susceptibility to BPH and that reducing inflammation with a therapeutic agent can suppress BPH.
Tissue infiltration and elevated peripheral circulation of granulocytic myeloid-derived cells is associated with poor outcomes in prostate cancer and other malignancies. Although myeloid-derived ...cells have the ability to suppress T-cell function, little is known about the direct impact of these innate cells on prostate tumor growth. Here, it is reported that granulocytic myeloid-derived suppressor cells (MDSC) are the predominant tumor-infiltrating cells in prostate cancer xenografts established in athymic nude mice. MDSCs significantly increased in number in the peripheral circulation as a function of xenograft growth and were successfully depleted
by Gr-1 antibody treatment. Importantly, MDSC depletion significantly decreased xenograft growth. We hypothesized that granulocytic MDSCs might exert their protumorigenic actions in part through neutrophil elastase (
), a serine protease released upon granulocyte activation. Indeed, it was determined that NE is expressed by infiltrating immune cells and is enzymatically active in prostate cancer xenografts and in prostate tumors of prostate-specific
-null mice. Importantly, treatment with sivelestat, a small-molecule inhibitor specific for NE, significantly decreased xenograft growth, recapitulating the phenotype of Gr-1 MDSC depletion. Mechanistically, NE activated MAPK signaling and induced MAPK-dependent transcription of the proliferative gene
in prostate cancer cells. Functionally, NE stimulated proliferation, migration, and invasion of prostate cancer cells
IHC on human prostate cancer clinical biopsies revealed coexpression of NE and infiltrating CD33
MDSCs.
This report suggests that MDSCs and NE are physiologically important mediators of prostate cancer progression and may serve as potential biomarkers and therapeutic targets.
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A practical, convergent synthesis of prostate‐specific membrane antigen (PSMA) targeted imaging agents for MRI, PET, and SPECT of prostate cancer has been developed. In this approach, metals chelated ...to 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) were placed on the side chains of lysine early in the synthesis to form imaging modules. These are coupled to targeting modules, in this case consisting of the PSMA‐binding urea DCL, bonded to an activated linker. The modular approach to targeted molecular imaging agents (TMIAs) offers distinct advantages. By chelating the MRI contrast metal Gd early, it doubles as a protecting group for DOTA. Standard coupling and deprotection steps may be utilized to assemble the modules into peptides, and the need for tri‐tert‐butyl protection of DOTA requiring removal by strong acid is averted. This enables mild conjugation of the imaging module to a wide variety of targeting agents in the final step. It was further discovered that two labile metals, La3+ or Ce3+, can be used as placeholders in DOTA during the synthesis, then transmetalated in mild acid by Cu2+, Ga3+, In3+, and Y3+, metals used in PET/SPECT. This enables the efficient synthesis of nonradioactive analogues of targeted molecular imaging agents that may be transported or stored until needed. A simple and mild two‐step transmetalation, involving de‐metalation in dilute acid, followed by rapid chelation of the radioactive metal, may be conveniently performed later at the clinic to provide the TMIAs for PET or SPECT.
A modular approach to the synthesis of targeted molecular imaging agents is described. A metal atom is introduced early on to form an imaging module for MRI or PET. This is coupled with a targeting module in a convergent step to form a selective imaging agent for prostate cancer.
Dear Editor, We present here a rare case of rectal adenocarcinoma metastasized to scrotum skin that was detected in a 36-year-old man. In addition, we have reviewed the Chinese and English literature ...for reports of internal malignancy secondary to scrotum skin. To our best knowledge, there are forty cases reported in literature.
The mainstay treatment for locally advanced, recurrent, or metastatic prostate cancer (PrCa) is androgen deprivation therapy (ADT). ADT causes prostate cancers to shrink in volume, or regress, by ...inducing epithelial tumor cell apoptosis. In normal, non-neoplastic murine prostate, androgen deprivation via castration induces prostate gland regression that is dependent on TNF signaling. In addition to this direct mechanism of action, castration has also been implicated in an indirect mechanism of prostate epithelial cell death, which has been described as vascular regression. The initiating event is endothelial cell apoptosis and/or increased vascular permeability. This subsequently leads to reduced blood flow and perfusion, and then hypoxia, which may enhance epithelial cell apoptosis. Castration-induced vascular regression has been observed in both normal and neoplastic prostates. We used photoacoustic, power Doppler, and contrast-enhanced ultrasound imaging, and CD31 immunohistochemical staining of the microvasculature to assess vascular integrity in the period immediately following castration, enabling us to test the role of TNF signaling in vascular regression. In two mouse models of androgen-responsive prostate cancer, TNF signaling blockade using a soluble TNFR2 ligand trap reversed the functional aspects of vascular regression as well as structural changes in the microvasculature, including reduced vessel wall thickness, cross-sectional area, and vessel perimeter length. These results demonstrate that TNF signaling is required for vascular regression, most likely by inducing endothelial cell apoptosis and increasing vessel permeability. Since TNF is also the critical death receptor ligand for prostate epithelial cells, we propose that TNF is a multi-purpose, comprehensive signal within the prostate cancer microenvironment that mediates prostate cancer regression following androgen deprivation.
Granulocytic myeloid infiltration and resultant enhanced neutrophil elastase (NE) activity is associated with poor outcomes in numerous malignancies. We recently showed that NE expression and ...activity from infiltrating myeloid cells was high in human prostate cancer xenografts and mouse
-null prostate tumors. We further demonstrated that NE directly stimulated human prostate cancer cells to proliferate, migrate, and invade, and inhibition of NE
attenuated xenograft growth. Interestingly, reduced expression of SERPINB1, an endogenous NE inhibitor, also correlates with diminished survival in some cancers. Therefore, we sought to characterize the role of SERPINB1 in prostate cancer. We find that SERPINB1 expression is reduced in human metastatic and locally advanced disease and predicts poor outcome. SERPINB1 is also reduced in
-null mouse prostate tumors compared with wild-type prostates, and treatment with sivelestat (SERPINB1 pharmacomimetic) attenuates tumor growth. Knockdown of highly expressed SERPINB1 in nonmalignant prostatic epithelial cells (RWPE-1) increases proliferation, decreases apoptosis, and stimulates expression of epithelial-to-mesenchymal transition markers. In contrast, stable SERPINB1 expression in normally low-expressing prostate cancer cells (C4-2) reduces xenograft growth
. Finally, EZH2-mediated histone (H3K27me3) methylation and DNA methyltransferase-mediated DNA methylation suppress SERPINB1 expression in prostate cancer cells. Analysis of The Cancer Genome Atlas and pyrosequencing demonstrate hypermethylation of the
promoter in prostate cancer compared with normal tissue, and the extent of promoter methylation negatively correlates with
mRNA expression. IMPLICATIONS: Our findings suggest that the balance between SERPINB1 and NE is physiologically important within the prostate and may serve as a biomarker and therapeutic target in prostate cancer.
First line treatment for recurrent and metastatic prostate cancer is androgen deprivation therapy (ADT). Use of ADT has been increasing in frequency and duration, such that side effects increasingly ...impact patient quality of life. One of the most significant side effects of ADT is sarcopenia, which leads to a loss of skeletal muscle mass and function, resulting in a clinical disability syndrome known as obese frailty. Using aged mice, we developed a mouse model of ADT-induced sarcopenia that closely resembles the phenotype seen in patients, including loss of skeletal muscle strength, reduced lean muscle mass, and increased adipose tissue. Sarcopenia onset occurred about 6 weeks after castration and was blocked by a soluble receptor (ActRIIB-Fc) that binds multiple TGFβ superfamily members, including myostatin, growth differentiation factor 11, activin A, activin B, and activin AB. Analysis of ligand expression in both gastrocnemius and triceps brachii muscles demonstrates that each of these proteins is induced in response to ADT, in 1 of 3 temporal patterns. Specifically, activin A and activin AB levels increase and decline before onset of strength loss at 6 weeks after castration, and myostatin levels increase coincident with the onset of strength loss and then decline. In contrast, activin B and growth differentiation factor 11 levels increase after the onset of strength loss, 8–10 weeks after castration. The observed patterns of ligand induction may represent differential contributions to the development and/or maintenance of sarcopenia. We hypothesize that some or all of these ligands are targets for therapy to ameliorate ADT-induced sarcopenia in prostate cancer patients.
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