Hormone Ablation Therapy Research Articles

Abstract 709: Enhancing prostate cancer treatment: Synergistic effects of mechano-thermal focused ultrasound and radiation therapy

Abstract Current treatments for prostate cancer primarily rely on radiation and hormone deprivation therapy, yet they often lack effective immunotherapeutic effects. Furthermore, long-term hormone ablation has side effects, such as, impotency and osteoporosis. Addressing this gap, we introduce an innovative dual-frequency focused ultrasound (FUS) platform for non-ablative focal therapy, which induces protein unfolding, ER stress, and increases heat-shock protein expression along with translocation of endoplasmic reticular chaperone proteins (e.g., calreticulin) on the tumor cell surface, thereby sensitizing them for phagocytosis by dendritic cells for efficient antigen presentation and cross priming. We hypothesized that FUS-mediated acoustic immune priming can be combined with ablative therapies, such as, hormone ablation and/or radiation therapy (RT) for induction of tumor-specific adaptive immune response and better tumor control than monotherapy in murine prostate cancer models. Utilizing murine prostate cancer cell lines, MyC-CaP and RM1, we explored the cellular responses to androgen deprivation, observing distinct sensitivities. Twenty-four hours after FUS treatment tumor cells experienced mechano-thermal stress response with 15-fold increase in Hspa1a expression. Transmission Electron Microscopy studies showed formation of myelin figures, nuclear membrane deformation, and lipid droplet formation. In vivo, the combination of FUS (220w/cm2 intensity for 3 sec at focal point) and RT (8-10 Gy daily x two fractions) markedly delayed tumor growth and achieved complete cure in 14-17% of animals. Through multicolor flow cytometry, we detected significant alterations in the immune microenvironment, including increased CD8+ T cell infiltration and reduced tumor-associated macrophages in the tumor bed. However, we also observed a compensatory rise in pro-tumor immune cells such as PMN-MDSCs and Tregs with significant suppression of eosinophils (p<0.05). Interestingly, there was suppression of splenic PMN-MDSCs, Mo-MDSCs, and tumor draining lymph node macrophages, suggesting systemic immune modulation in peripheral lymphoid organs of FUS+RT-treated tumor-bearing animals. Our findings reveal that the combination therapy of FUS and RT improves tumor control in murine prostate cancer and significantly modulates the systemic and tumor immune microenvironment. This approach offers new avenues for immunotherapy, potentially transforming the treatment landscape for prostate cancer, typically resistant to conventional immunotherapeutic strategies. Citation Format: Soumya Chatterjee, Saurabh Singh, Stephen Barry, Chandan Guha. Enhancing prostate cancer treatment: Synergistic effects of mechano-thermal focused ultrasound and radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 709.

OP70 Treating Patients With Hormone-Sensitive Cancer On Endocrine Therapy With Denosumab (Prolia®): A Systematic Review And Network Meta-Analysis

IntroductionPatients receiving endocrine therapy for hormone-sensitive cancers, such as men with prostate cancer (MPC) on hormone ablation therapy (HAT) and women with breast cancer (WBC) on adjuvant aromatase inhibitor therapy (AAIT), have an increased risk of developing osteoporosis. The aim of this study was to compare the safety and effectiveness of denosumab (Prolia®) with selective estrogen receptor modulators (SERMs) (raloxifene and bazedoxifene), bisphosphonates (zoledronate, ibandronate, alendronate, and risedronate), and placebo for the treatment of osteoporosis in patients receiving endocrine therapy for hormone-sensitive cancer.MethodsSystematic literature searches were conducted in three biomedical databases (PubMed, the Cochrane Library, and Embase) to identify randomized controlled trials (RCTs). Only RCTs that investigated MPC on HAT or WBC on AAIT allocated to denosumab, SERMs, bisphosphonates, or placebo were included. RCTs were appraised using the Cochrane Risk of Bias 2.0 tool. Frequentist network and pairwise meta-analyses were performed on predetermined outcomes of vertebral or nonvertebral fractures, treatment-related adverse events (AEs), bone mineral density (BMD), mortality, withdrawal due to treatment-related AEs, and serious AEs.ResultsA total of 14 RCTs (15 publications, 6,463 participants) were included. Relative to placebo, denosumab was found to prevent vertebral fractures in cancer patients receiving endocrine therapy. Moreover, denosumab, alendronate, and zoledronate increased femoral neck (FN) and lumbar spine (LS) BMD in MPC on HAT, compared with placebo, whereas denosumab, risedronate, and ibandronate improved LS and total hip BMD in WBC on AAIT. Similarly, denosumab and risedronate increased trochanteric BMD in WBC on AAIT, compared with placebo. In WBC on AAIT, only denosumab increased FN BMD relative to placebo.ConclusionsDenosumab was more effective than placebo in preventing vertebral fractures and improving BMD at the LS and FN in MPC on HAT, and in preventing vertebral fractures and improving FN, trochanteric, total hip, and LS BMD in WBC on AAIT. From a policy perspective, the continued reimbursement of denosumab needs to be reviewed.

Systematic Evaluation of Studies in the Fields of Diagnosis and Management of Prostate Cancer in Coronavirus Disease 2019 Era

Background: Prostate cancer is one of the most common cancers worldwide. The proper management of this cancer during the coronavirus disease 2019 (COVID-19) or similar outbreaks could be a serious challenge. Proper timing of surgery, radiotherapy, and other medical modalities are essential in providing the most effective treatment. Objectives: This systematic review aimed at evaluating the proper management of prostate cancer during the COVID-19 outbreak. Methods: This study was conducted from 2019 to 2022. An internet search was conducted using the keywords: Diagnosis, management, radical prostatectomy, radiotherapy, hormone ablation therapy, chemotherapy and prostate cancer, and COVID-19. The visited databases included PubMed, Scopus, Web of Sciences, Google Scholar, and Scientific Information Database. The review was performed based on the preferred reporting items for a systematic review and meta-analyses (PRISMA) guidelines. Results: Postponing the biopsy for up to three months and adopting of non-invasive diagnostic methods were likely reasonable during the COVID-19 pandemic. Patients with cancer were more prone to severe injuries and were more likely to have serious complications. Surgery, radiation therapy, brachytherapy, palliative radiation, hormone ablation therapy, and chemotherapy were among the pre-institutional treatments that had to be performed according to medical protocols as well as health and professional guidelines. Conclusions: It was recommended that the prostate cancer screening should not be performed for asymptomatic men during the COVID-19 outbreak. It was also suggested that the treatment should be performed in the shortest possible time and in the safest way.

The clinical effectiveness of denosumab (Prolia®) in patients with hormone-sensitive cancer receiving endocrine therapy, compared to bisphosphonates, selective estrogen receptor modulators (SERM), and placebo: a systematic review and network meta-analysis.

This study assessed the effectiveness and safety of denosumab (Prolia®) compared to bisphosphonates (alendronate, ibandronate, risedronate, zoledronate), selective estrogen receptor modulators (SERMs) (bazedoxifene, raloxifene) and placebo for the treatment of osteoporosis in hormone-sensitive cancer patients receiving endocrine therapy (men with prostate cancer [MPC] on hormone ablation therapy [HAT], and women with breast cancer [WBC] on adjuvant aromatase inhibitor therapy [AAIT]). Systematic literature searches were conducted in three biomedical databases to identify randomized controlled trials (RCTs). Frequentist network meta-analyses and/or pairwise meta-analyses were performed on predetermined outcomes (i.e., vertebral/nonvertebral fractures, bone mineral density [BMD], mortality, treatment-related adverse events [AEs], serious AEs [SAEs], withdrawal due to treatment-related AEs). A total of 14 RCTs (15 publications) were included. Denosumab was found to prevent vertebral fractures in cancer patients receiving endocrine therapy, relative to placebo. Similarly, denosumab, zoledronate, and alendronate improved BMD at the femoral neck (FN) and lumbar spine (LS) in MPC on HAT, relative to placebo. Denosumab, ibandronate and risedronate improved BMD at the LS and total hip (TH) in WBC on AAIT, relative to placebo. Denosumab and risedronate improved trochanteric (TRO) BMD in WBC on AAIT, relative to placebo. Similarly, denosumab improved FN BMD in WBC on AAIT. In MPC on HAT, denosumab (relative to placebo) was effective at preventing vertebral fractures and improving BMD at the FN and LS. Moreover, in WBC on AAIT, denosumab (relative to placebo) improved BMD at the FN, LS, TH, and TRO, as well as prevent vertebral fracture.

Crosstalk between epigenetics and tumor promoting androgen signaling in prostate cancer.

Prostate cancer (PCa) is one of the major health burdens among all cancer types in men globally. Early diagnosis and efficacious treatment options are highly warranted as far as the incidence of PCa is concerned. Androgen-dependent transcriptional activation of androgen receptor (AR) is central to the prostate tumorigenesis and therefore hormonal ablation therapy remains the first line of treatment for PCa in the clinics. However, the molecular signaling engaged in AR-dependent PCa initiation and progression is infrequent and diverse. Moreover, apart from the genomic changes, non-genomic changes such as epigenetic modifications have also been suggested as critical regulator of PCa development. Among the non-genomic mechanisms, various epigenetic changes such as histones modifications, chromatin methylation and noncoding RNAs regulations etc. play decisive role in the prostate tumorigenesis. Given that epigenetic modifications are reversible using pharmacological modifiers, various promising therapeutic approaches have been designed for the better management of PCa. In this chapter, we discuss the epigenetic control of tumor promoting AR signaling that underlies the mechanism of prostate tumorigenesis and progression. In addition, we have discussed the approaches and opportunities to develop novel epigenetic modifications based therapeutic strategies for targeting PCa including castrate resistant prostate cancer (CRPC).

PD13-03 MORTALITY FROM SECONDARY CANCERS IN MEN TREATED WITH RADICAL PROSTATECTOMY FOR PROSTATE CANCER: AN INSIGHT INTO PROSTATE CANCER SURVIVORSHIP AT 15-YEARS OF FOLLOW-UP

You have accessJournal of UrologyProstate Cancer: Epidemiology & Natural History I (PD13)1 Sep 2021PD13-03 MORTALITY FROM SECONDARY CANCERS IN MEN TREATED WITH RADICAL PROSTATECTOMY FOR PROSTATE CANCER: AN INSIGHT INTO PROSTATE CANCER SURVIVORSHIP AT 15-YEARS OF FOLLOW-UP Akshay Sood, Mireya Diaz, Wooju Jeong, Mohit Butaney, Anudeep Mukkamala, James Peabody, Hans Stricker, Craig Rogers, Firas Abdollah, and Mani Menon Akshay SoodAkshay Sood More articles by this author , Mireya DiazMireya Diaz More articles by this author , Wooju JeongWooju Jeong More articles by this author , Mohit ButaneyMohit Butaney More articles by this author , Anudeep MukkamalaAnudeep Mukkamala More articles by this author , James PeabodyJames Peabody More articles by this author , Hans StrickerHans Stricker More articles by this author , Craig RogersCraig Rogers More articles by this author , Firas AbdollahFiras Abdollah More articles by this author , and Mani MenonMani Menon More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001989.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: With advances in surgical and medical care, and an overall increase in life-expectancy, survivorship in men with prostate cancer (CaP) is of emerging relevance. We sought to examine 15-year secondary cancer and CaP related mortality in men treated with radical prostatectomy (RP) as their initial treatment for CaP. METHODS: Between September 2001 and December 2013, 6,060 men underwent robot-assisted RP (RARP) as first-line therapy for clinically confined CaP at our institution. The patients were stratified by burden of comorbidity (using age-adjusted Charlson comorbidity index [CCI]) and tumor-specific risk (Diaz classification [risk groups 1-5], details in Figure 1) into 12 groups, and mortality from CaP, secondary cancers, non-oncologic causes and unknown causes were estimated using competing risk analysis within these groups. RESULTS: The median follow-up was 8 years. At 15-years, 9% of the patients had developed secondary cancers and 1.5% had died from them. Further, secondary cancers were the leading cause of death in men in Diaz risk groups 1-3 (Figure 1 a-f), with the risk of death increasing with the burden of comorbidity (secondary cancer specific mortality rate at 15-year was between 1.1 and 7.7% depending on the CCI score). The top 3 secondary malignancies were lung, colon, and pancreas and hematologic cancers (the latter two tied for the 3rd place). Family h/o of CaP, family h/o cancers other than CaP, and use of post-RP hormone ablation or radiation therapy were not associated with increased risk of secondary malignancies. CONCLUSIONS: Secondary cancers develop in 9% of post-RP patients with 1.5% dying of them within 15-years. In men with low and favorable intermediate risk CaP, secondary cancers represent the major cause of mortality (none of these men die of CaP). These data have clinical significance with regards to patient counseling, survivorship, and oncologic surveillance in the CaP population that choose RP as their initial treatment. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e210-e210 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Akshay Sood More articles by this author Mireya Diaz More articles by this author Wooju Jeong More articles by this author Mohit Butaney More articles by this author Anudeep Mukkamala More articles by this author James Peabody More articles by this author Hans Stricker More articles by this author Craig Rogers More articles by this author Firas Abdollah More articles by this author Mani Menon More articles by this author Expand All Advertisement PDF downloadLoading ...

S2958 Endometriomas as the Cause of Abdominal Wall Masses in a Woman With Cyclical Abdominal Pain

INTRODUCTION: Endometriosis is characterized by the presence of endometrial tissue outside the uterine cavity. When endometriosis forms a distinct mass, it is termed an endometrioma. Extra-pelvic endometriosis is rare, accounting for less than 12% of reported cases. Among these, one of the rarest forms is abdominal wall endometriosis. The diagnosis of abdominal wall endometriosis can be challenging, and requires a high index of suspicion. CASE DESCRIPTION/METHODS: A 48-year-old woman with a history of a locally treated left second toe melanoma and a previous cesarean section (C-section) presented for evaluation of cyclic abdominal pain of several years duration. Her discomfort was localized to the right lower quadrant associated with her menstrual period. Physical examination revealed two tender small nodules, one in the right lower quadrant and one in the midline approximately at the level of her prior C-section scar. CT imaging of the abdomen/pelvis performed at an outside institution demonstrated two nodules along the abdominal wall associated with the musculature measuring 2.2- and 1.5-cm in diameter (Images 1 and 2). Locally, a laparoscopy was normal revealing no evidence of endometriosis. Given her previous history of melanoma and to also rule out the possibility of desmoid tumor, we proceeded with an ultrasound-guided biopsy. Histopathology demonstrated fibrous tissue involved by endometriosis in the area along the prior C-section scar (Image 3). She was evaluated by gynecology and general surgery to discuss oral contraceptives, ablative therapy, or surgical resection, and decided on hormonal therapy as initial treatment. DISCUSSION: Abdominal wall endometriosis has a reported incidence of 0.03–1.5% following C-section or pelvic surgery. Symptom fluctuation with the menstrual cycle and presence of gynecologic surgical scars are important clues hinting at the diagnosis. The clinical diagnosis of abdominal wall endometrioma has been confused with abscess, lipoma, hernia, desmoid tumor, or primary and metastatic malignancies. Ultrasound, CT imaging, and MRI are useful noninvasive techniques when the diagnosis is unclear. Percutaneous biopsy can yield a definitive diagnosis. Therapies include hormonal treatment, ablative therapy, or surgical resection. This novel case highlights the importance of considering abdominal wall endometrioma in the differential diagnosis when evaluating women with an abdominal wall mass and a history of uterine surgery with cyclic abdominal pain.Figure 1.: CT scan of the abdomen and pelvis demonstrating two nodules along the abdominal wall associated with the musculature measuring 2.2- and 1.5-cm in diameter.Figure 2.: CT scan of the abdomen and pelvis demonstrating two nodules along the abdominal wall associated with the musculature measuring 2.2- and 1.5-cm in diameter.Figure 3.: Hematoxylin and eosin stain of US-guided biopsy tissue specimen from abdominal wall nodule demonstrating benign endometrial glands and stroma.

Abstract 1984: Anisotropy of collagen I matrix influences therapeutic response and secretome of Luminal A cells

Abstract High degree of collagen I fiber orientation has been associated with guided tumor cell invasion, but little is known about its impact in therapeutic response. Anisotropic substrates have been shown to influence the phenotype of stem cells which suggests that it can influence tumor cell behavior beyond cell migration. We hypothesized that the anisotropy of collagen I matrix impacts therapeutic response by modulating the secretome of breast cancer cells and this effect is mediated by integrin signaling. To test our hypothesis, the cell secretome, response to hormone ablation therapy and integrin inhibitors were evaluated in breast tumor cells cultured in collagen type 1 substrates of defined orientation. The orientation of electrospun collagen I fibrils was regulated by adjusting the syringe flow rate and collector velocity to obtain random (<70%) or aligned (>80%) oriented fibrils. Average porosity (45± 3.4 %), matrix stiffness (0.8 ±0.24 MPa) and fiber diameter (1.6 ± 0.86μm) were kept constant across collagen substrates. Estrogen-dependent Luminal A cells (MCF-7 and T-47D) cells were cultured on collagen substrates in a hormone-deprived environment for 3-6 days. Polycaprolactone (PCL) fibrous substrates of aligned and random orientation were used as negative fibrous controls for integrin signaling. Evaluation of cell growth showed that a fibrillar structure in combination with a high degree of fibril orientation significantly increased cell proliferation (>75%) as compared to gelatin-coated tissue culture plastic (TCP). Collagen fibers significantly supported hormone-independent tumor growth at levels equivalent to or above those observed in the estrogen-treated control. Increased proliferation levels were supported on collagen fibrous substrates treated with Tamoxifen and Fulvestrant, and this effect was enhanced in aligned collagen I. Inhibition of α2β1 integrin resulted in enhanced proliferation rates in random fibers and suppression of cell growth in aligned fibers. PCL aligned substrates where not sufficient to support hormone-independent cell growth. MCF-7 cells on collagen substrates significantly stimulated the growth (>7 fold) of adjacent cells on TCP in a dose-response manner as follows: aligned > random > gelatin. Expression levels of 1000 factors were quantified in conditioned medium to identify differences in the secretome signatures associated with cell-matrix signaling. MCF-7 cells cultured on collagen fibrous substrates displayed secretome signatures that were different across all substrates. Fourteen factors were identified to be upregulated in fibrous substrates by more than ten folds including apoptotic regulators RalA and BCL-2. Our results show for the first time the influence of collagen I fibril orientation in supporting hormone-independent growth and as a novel regulator therapeutic response in luminal A cells. Citation Format: Ana M. Reyes, Jorge Almodovar, Elaine Alarid, Maribella Domenech. Anisotropy of collagen I matrix influences therapeutic response and secretome of Luminal A cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1984.

Oophorectomy as a Hormonal Ablation Therapy in Metastatic and Recurrent Breast Cancer: Current Indications and Results.

Breast cancer is the commonest malignancy affecting females. Hormone-positive cancers carry a better prognosis. Many adjuvant and palliative endocrine therapies are in use, including surgical ablation. We retrospectively studied seventy-four patients who did bilateral salpingo-oophorectomy (BSO)/bilateral oophorectomy (BO) for factors affecting survival and prognosis. BSO was superior in overall and progression-free survival. Incidental ovarian metastasis carried a grave prognosis. Surgical hormonal ablation is a viable option with laparoscopic BSO as the approach of choice.

Abstract B56: Regulation of CXCR5-CXCL13 signaling in prostate cancer etiologic disparities

Abstract The prevalence of prostate cancer (PCa) has been a worldwide burden. Cancer of the prostate is the most prevalent form of cancer in men and the second leading cause of death due to cancer in men in the United States and Europe. There is a major health disparity associated with PCa; the number of fatalities associated with this disease is more significant in African-American (AA) men than in European American (EA) men. Disease progression occurs despite hormone ablation therapy, which leads to a condition called castration-resistant prostate cancer (CRPC). Further complicating the matter, CRPC is a disease that affects a variety of patients differently, which can be problematic for physicians to provide standardized treatments with similar outcomes. AAs with CRPC can experience significantly lower rates of overall survival, faster rates of tumor progression, and poor responses to chemotherapy compared to EAs with this disease. We previously showed that CXCL13:CXCR5 axis plays a role in PCa pathobiology and is also associated with PCa aggressiveness; CXCR5 signaling mediates PCa cell growth, migration, invasion, and docetaxel resistance. To further understand the implication of CXCR5-CXCL13 in CRPC, we characterize the reason behind the health disparities seen across groups of PCa patients by evaluating the difference in regulatory molecules (miRNAs) on CXCL13-CXCR5 signaling. We found the expression profile of CXCL13 and CXCR5 RNA to be associated with miRNAs (miR-140-3p.1, miR-24-3p, miR-200c, miR-221-3p/22-3p, miR-192-5p/215-5p, miR-214-5p). Using RNA-seq datasets from the Gene Expression Omnibus (GEO) and the Sequence Read Archive (SRA), CXCL13 and CXCR5 RNA as well as associated miRNAs (miR-140-3p.1, miR-24-3p, miR-221-3p/22-3p, miR-192-5p/215-5p, and miR-214-5p) were defined by etiologic disparities among PCa patients; this correlation is different among AA men compared to EA men. Understanding PCa and specifically CRPC disparities requires a better understanding of the race-specific differences in prostate tumor biology, molecules leading to prostate inflammation, and the mechanisms associated with CRPC therapeutic resistance and its aggressive phenotype. Citation Format: Adaugo Queen Ohandjo, Courtney Dill, Chen Dongquan, James W. Lillard, Jr.. Regulation of CXCR5-CXCL13 signaling in prostate cancer etiologic disparities [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B56.

Describing Symptom Burden and Functional Status at the Diagnosis of Leptomeningeal Metastasis.

To investigate the associations of primary cancer, tumor characteristics, and cancer treatment with symptom burden and functional status. 52 patients with leptomeningeal metastasis (LM) at the University of Texas MD Anderson Cancer Center in Houston. Records of 52 patients were reviewed, and presenting symptoms were recorded. Mean differences in number and specific symptoms and functional status were explored. Correlations between age and overall number of symptoms with specific symptoms were assessed with Pearson correlations. Pain was the most frequently reported symptom. Hormonal ablation therapy within six months of LM diagnosis was associated with a higher number of symptoms. Receiving biotherapy more than six months prior to an LM diagnosis was associated with pain, and cerebrospinal fluid leukocytosis was associated with a poor Karnofsky Performance Status score. Nurses caring for patients with advanced cancer can help ensure the highest possible quality of life by obtaining a careful history, assessing symptoms, and noting any changes since the last encounter.

Is DCIS Overrated?

Ductal carcinoma in situ (DCIS), the noninvasive form of breast cancer (BC), comprises just over 20% of breast cancer cases diagnosed each year in the USA. Most patients are treated with local excision of the disease followed by whole breast radiation therapy. Total mastectomy is not an uncommon approach, and total mastectomy with a contralateral risk-reducing mastectomy has been on the rise in the past decade. In estrogen receptor-positive disease, patients are often offered endocrine ablative therapy with a selective estrogen receptor modulator or an aromatase inhibitor as both treatment and prevention. Local regional treatment options have no impact upon ultimate overall survival. Long-term survival rates are higher in patients with DCIS than with any other form of the disease. Are these strikingly high success rates a testament to effective treatment strategies or is there a significant subset of DCIS that was unlikely to ever progress to invasive ductal carcinoma? DCIS was not seen in the US prior to the advent of screening mammography. When compared to other countries, the USA has the highest utilization of screening mammography and the incidence rate of DCIS. Other lines of evidence include autopsy series examining the breast tissue of women who died of other causes, missed-diagnosis series and current retrospective reviews of DCIS, all align in support of the concept of DCIS as indolent in the majority of cases [3-14]. The evidence suggests that both patient and physician misconceptions about DCIS have led to overdiagnosis and over-treatment of DCIS. Recently, a gene expression profiling tool (12 gene assay, Oncotype DCIS) has emerged that shows considerable promise in predicting class in DCIS patients.

C-Met/miR-130b axis as novel mechanism and biomarker for castration resistance state acquisition.

Although a significant subset of prostate tumors remain indolent during the entire life, the advanced forms are still one of the leading cause of cancer-related death. There are not reliable markers distinguishing indolent from aggressive forms. Here we highlighted a new molecular circuitry involving microRNA and coding genes promoting cancer progression and castration resistance. Our preclinical and clinical data demonstrated that c-Met activation increases miR-130b levels, inhibits androgen receptor expression, promotes cancer spreading and resistance to hormone ablation therapy. The relevance of these findings was confirmed on patients' samples and by in silico analysis on an independent patient cohort from Taylor's platform. Data suggest c-Met/miR-130b axis as a new prognostic marker for patients' risk assessment and as an indicator of therapy resistance. Our results propose new biomarkers for therapy decision-making in all phases of the pathology. Data may help identify high-risk patients to be treated with adjuvant therapy together with alternative cure for castration-resistant forms while facilitating the identification of possible patients candidates for anti-Met therapy. In addition, we demonstrated that it is possible to evaluate Met/miR-130b axis expression in exosomes isolated from peripheral blood of surgery candidates and advanced patients offering a new non-invasive tool for active surveillance and therapy monitoring.

Could Denosumab Support Bone Integrity in Sickle Cell Disease

Sickle cell anaemia is a congenital disease characterized by painful vaso-occlusive crises. It is associated with vitamin D deficiency, osteoporosis and recurrent attacks of micro-infarctions lead to bone osteonecrosis. The most common sites of osteonecrosis in sickle cell disease are the femoral and humeral heads which could lead to severe pain and extensive physical disability. Denosumab is a new human monoclonal antibody product; it is a receptor activator of nuclear factor kappa B ligand RANKL. That decreases osteoclastic bone restoration. It is Food and Drug Administration FDA approved for osteoporosis for women with high risk of fracture; and it is also being used for the treatment and prevention of bone loss in patients undergoing hormone ablation therapy for breast and prostate cancer. Denosumab is not restricted for sickle cell disease patients within its approved indications. It has less nephrotoxicity effect than the bisphosphonates which is a big advantage for sickle cell patients. It also used as an adjuvant agent to reduce metastatic bone pain in solid tumors. The extension of Denosumab use for sickle cell patients’ osteoporosis and osteonecrosis deserve a randomized multi central trail aiming to improve bone integrity and possible reduction of the devastating pain in sickle cell disease patients.

Maintenance Therapy Containing Metformin and/or Zyflamend for Advanced Prostate Cancer: A Case Series.

Metformin is derived from galegine, a natural ingredient, and recent studies have suggested that metformin could enhance the antitumor effects of hormone ablative therapy or chemotherapy and reduce prostate cancer-specific mortality. Zyflamend is a combination of herbal extracts that reduces inflammation and comprises turmeric, holy basil, green tea, oregano, ginger, rosemary, Chinese goldthread, hu zhang, barberry, and basil skullcap. We propose a maintenance regimen with metformin and/or Zyflamend that targets cancer stem cells and the tumor microenvironment to keep the cancer dormant and prevent it from activation from dormancy. Herein, we report the clinical course of four patients who experienced a clinical response after treatment with metformin and/or Zyflamend.

Targeting bone metabolism in patients with advanced prostate cancer: current options and controversies.

Maintaining bone health remains a clinical challenge in patients with prostate cancer (PC) who are at risk of developing metastatic bone disease and increased bone loss due to hormone ablation therapy. In patients with cancer-treatment induced bone loss (CTIBL), antiresorptive agents have been shown to improve bone mineral density (BMD) and to reduce the risk of fractures. For patients with bone metastases, both zoledronic acid and denosumab delay skeletal related events (SREs) in the castration resistant stage of disease. Novel agents targeting the Wnt inhibitors dickkopf-1 and sclerostin are currently under investigation for the treatment of osteoporosis and malignant bone disease. New antineoplastic drugs such as abiraterone, enzalutamide, and Radium-223 are capable of further delaying SREs in patients with advanced PC. The benefit of antiresorptive treatment for patients with castration sensitive PC appears to be limited. Recent trials on the use of zoledronic acid for the prevention of bone metastases failed to be successful, whereas denosumab delayed the occurrence of bone metastases by a median of 4.1 months. Currently, the use of antiresorptive drugs to prevent bone metastases still remains a field of controversies and further trials are needed to identify patient subgroups that may profit from early therapy.

Abstract 3423: The genomic evolution of prostate cancer under the selective pressure of anti-androgen therapy

Abstract Background The implementation of novel technologies such as array comparative genomic hybridization (aCGH) and next-generation sequencing has led to a deeper understanding of the genomic nature of cancer. However, these analyses have classically been done without respecting intra-tumor heterogeneity. Here, we applied a methodology that allows us analyzing the genomic profile of distinct tumor populations from individual tumors and their clonal evolution during the progression to castration-resistant disease, thus enabling the discovery of novel genetic alterations in the course of the development of therapy resistance. Methods Matched pre- and post- hormone treated fresh frozen and/or formalin fixed prostate cancer samples were selected from our biobank. Clonal tumor populations were flow-sorted according to their nuclear DNA content. Sorted tumor populations were subjected to whole genome CGH and to full exome sequencing analyses by the use of Agilent SurePrint 2x400k microarrays and the SureSelect All Exon Kit, respectively. Target aberrations were evaluated using a prostate cancer tissue micro array (TMA) and fluorescence in situ hybridization as well as immunohistochemistry. Results The de-convolution of the genomic evolution in the investigated tumors shows that genetic aberrations and mutations are newly occurring under the selective pressure of anti-androgen therapy. More importantly, judging on the temporal dynamics of changes in allelic frequencies, we cannot only observe events that become more abundant, but also cancer associated mutations that are negatively selected for. We are currently following up several of these targets, of which at least one shows significant association with overall survival and differences in its expression pattern between hormone naïve and castration resistant cancer. Conclusions Genomic profiling of distinct clonal tumor populations during prostate cancer progression allows for analysis of intra-tumoral heterogeneity and the underlying clonal evolution. Importantly, this approach identifies genomic aberrations that were selected for under the pressure of hormone ablation therapy. Citation Format: Joël Roman Gsponer, Tanja Dietsche, Alexander Rufle, Thomas Lorber, Darius Juskevicius, Valeria Perrina, Elisabeth Lenkiewicz, Tobias Zellweger, Alexander Bachmann, Michael T. Barrett, Cyrill A. Rentsch, Christian Ruiz, Lukas Bubendorf. The genomic evolution of prostate cancer under the selective pressure of anti-androgen therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3423. doi:10.1158/1538-7445.AM2014-3423

Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts.

Prostate cancer (PC) is a slowly progressing malignancy that often responds to androgen ablation or chemotherapy by becoming more aggressive, acquiring a neuroendocrine phenotype, and undergoing metastatic spread. We found that B lymphocytes recruited into regressing androgen-deprived tumors by C-X-C motif chemokine 13 (CXCL13), a chemokine whose expression correlates with clinical severity, play an important role in malignant progression and metastatic dissemination of PC. We now describe how androgen ablation induces CXCL13 expression. In both allografted and spontaneous mouse PC, CXCL13 is expressed by tumor-associated myofibroblasts that are activated on androgen ablation through a hypoxia-dependent mechanism. The same cells produce CXCL13 after chemotherapy. Myofibroblast activation and CXCL13 expression also occur in the normal prostate after androgen deprivation, and CXCL13 is expressed by myofibroblasts in human PC. Hypoxia activates hypoxia-inducible factor 1 (HIF-1) and induces autocrine TGF-β signaling that promotes myofibroblast activation and CXCL13 induction. In addition to TGF-β receptor kinase inhibitors, myofibroblast activation and CXCL13 induction are blocked by phosphodiesterase 5 (PDE5) inhibitors. Both inhibitor types and myofibroblast immunodepletion block the emergence of castration-resistant PC in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of spontaneous metastatic PC with neuroendocrine differentiation.

Polysaccharopeptide enhanced the anti-cancer effect of gamma-tocotrienol through activation of AMPK.

BackgroundProstate cancer (PCa) frequently relapses after hormone ablation therapy. Unfortunately, once progressed to the castration resistant stage, the disease is regarded as incurable as prostate cancer cells are highly resistant to conventional chemotherapy.MethodWe recently reported that the two natural compounds polysaccharopeptide (PSP) and Gamma-tocotrienols (γ-T3) possessed potent anti-cancer activities through targeting of CSCs. In the present study, using both prostate cancer cell line and xenograft models, we seek to investigate the therapeutic potential of combining γ-T3 and PSP in the treatment of prostate cancer.ResultWe showed that in the presence of PSP, γ-T3 treatment induce a drastic activation of AMP-activated protein kinase (AMPK). This was accompanied with inactivation of acetyl-CoA carboxylase (ACC), as evidenced by the increased phosphorylation levels at Ser 79. In addition, PSP treatment also sensitized cancer cells toward γ-T3-induced cytotoxicity. Furthermore, we demonstrated for the first time that combination of PSP and γ-T3 treaments significantly reduced the growth of prostate tumor in vivo.ConclusionOur results indicate that PSP and γ-T3 treaments may have synergistic anti-cancer effect in vitro and in vivo, which warrants further investigation as a potential combination therapy for the treatment of cancer.

Luteolin, ellagic acid and punicic acid are natural products that inhibit prostate cancer metastasis.

Prostate cancer (PCa) is the second cause of cancer deaths in men in the USA. When the cancer recurs, early stages can be controlled with hormone ablation therapy to delay the rate of cancer progression but, over time, the cancer overcomes its hormone dependence, becomes highly aggressive and metastasizes. Clinical trials have shown that pomegranate juice (PJ) inhibits PCa progression. We have previously shown that the PJ components luteolin (L), ellagic acid (E) and punicic acid (P) together inhibit growth of hormone-dependent and -independent PCa cells and inhibit their migration and chemotaxis towards CXCL12, a chemokine that is important in PCa metastasis. On the basis of these findings, we hypothesized that L+E+P inhibit PCa metastasis in vivo. To test this possibility, we used a severe combined immunodeficiency mouse model in which luciferase-expressing human PCa cells were injected subcutaneously near the prostate. Tumor progression was monitored with bioluminescence imaging weekly. We found that L+E+P inhibits PC-3M-luc primary tumor growth, inhibits the CXCL12/CXCR4 axis for metastasis and none of the tumors metastasized. In addition, L+E+P significantly inhibits growth and metastasis of highly invasive Pten (-/-) ;K-ras (G12D) prostate tumors. Furthermore, L+E+P inhibits angiogenesis in vivo, prevents human endothelial cell (EC) tube formation in culture and disrupts preformed EC tubes, indicating inhibition of EC adhesion to each other. L+E+P also inhibits the angiogenic factors interleukin-8 and vascular endothelial growth factor as well as their induced signaling pathways in ECs. In conclusion, these results show that L+E+P inhibits PCa progression and metastasis.