Heterogeneous cancer-associated fibroblast population potentiates neuroendocrine differentiation and castrate resistance in a CD105-dependent manner.

Heterogeneous prostatic carcinoma-associated fibroblasts (CAF) contribute to tumor progression and resistance to androgen signaling deprivation therapy (ADT). CAF subjected to extended passaging, compared to low passage CAF, were found to lose tumor expansion potential and heterogeneity. Cell surface endoglin (CD105), known to be expressed on proliferative endothelia and mesenchymal stem cells, was diminished in high passage CAF. RNA-sequencing revealed SFRP1 to be distinctly expressed by tumor-inductive CAF, which was further demonstrated to occur in a CD105-dependent manner. Moreover, ADT resulted in further expansion of the CD105+ fibroblastic population and downstream SFRP1 in 3-dimensional cultures and patient-derived xenograft tissues. In patients, CD105+ fibroblasts were found to circumscribe epithelia with neuroendocrine differentiation. CAF-derived SFRP1, driven by CD105 signaling, was necessary and sufficient to induce prostate cancer neuroendocrine differentiation in a paracrine manner. A partially humanized CD105 neutralizing antibody, TRC105, inhibited fibroblastic SFRP1 expression and epithelial neuroendocrine differentiation. In a novel synthetic lethality paradigm, we found that simultaneously targeting the epithelia and its microenvironment with ADT and TRC105, respectively, reduced castrate-resistant tumor progression, in a model where either ADT or TRC105 alone had little effect

Cancer epithelia-derived mitochondrial DNA is a targetable initiator of a paracrine signaling loop that confers taxane resistance.

Stromal-epithelial interactions dictate cancer progression and therapeutic response. Prostate cancer (PCa) cells were identified to secrete greater concentration of mitochondrial DNA (mtDNA) compared to noncancer epithelia. Based on the recognized coevolution of cancer-associated fibroblasts (CAF) with tumor progression, we tested the role of cancer-derived mtDNA in a mechanism of paracrine signaling. We found that prostatic CAF expressed DEC205, which was not expressed by normal tissue-associated fibroblasts. DEC205 is a transmembrane protein that bound mtDNA and contributed to pattern recognition by Toll-like receptor 9 (TLR9). Complement C3 was the dominant gene targeted by TLR9-induced NF-κB signaling in CAF. The subsequent maturation complement C3 maturation to anaphylatoxin C3a was dependent on PCa epithelial inhibition of catalase in CAF. In a syngeneic tissue recombination model of PCa and associated fibroblast, the antagonism of the C3a receptor and the fibroblastic knockout of TLR9 similarly resulted in immune suppression with a significant reduction in tumor progression, compared to saline-treated tumors associated with wild-type prostatic fibroblasts. Interestingly, docetaxel, a common therapy for advanced PCa, further promoted mtDNA secretion in cultured epithelia, mice, and PCa patients. The antiapoptotic signaling downstream of anaphylatoxin C3a signaling in tumor cells contributed to docetaxel resistance. The inhibition of C3a receptor sensitized PCa epithelia to docetaxel in a synergistic manner. Tumor models of human PCa epithelia with CAF expanded similarly in mice in the presence or absence of docetaxel. The combination therapy of docetaxel and C3 receptor antagonist disrupted the mtDNA/C3a paracrine loop and restored docetaxel sensitivity

Treatment strategies and clinical outcomes of locally advanced pancreatic cancer patients treated at high-volume facilities and academic centers.

PurposeLocally advanced pancreatic cancer (LAPC) treatment has varying practice patterns with poor outcomes. We investigated treatment using single-agent chemotherapy and multiagent chemotherapy (MAC) with or without radiation therapy (RT) at high-volume facilities (HVFs) and academic centers (ACs).Methods and materialsThe National Cancer Database was used to obtain data on 10,139 patients with LAPC. HVF was defined as the top 5% of facilities per number of patients treated at each facility. Univariate and multivariable (MVA) analysis Cox regressions were performed to identify the impact of HVF, AC, MAC, and RT on overall survival (OS).ResultsThe median age of patients was 66 years (range, 22-90); 50.1% were male and 49.9% female. Of the patients, 46.1% received MAC, 53.8% received single-agent chemotherapy, 45.7% received RT, 54.3% did not receive RT, and 5% underwent surgical resection. The median follow-up was 48.8 months. On MVA, treatment at HVFs and ACs remained significantly associated with improved OS, with a hazard ratio (HR) of 0.84 (P < .001) and 0.94 (P = .004), respectively. The median OS for HVF treatment compared with low-volume facilities was 14.3 versus 11.2 months, respectively (P < .001). The median OS for AC treatment versus non-AC was 12.1 versus 10.8 months, respectively (P < .001). Additionally, on MVA, receipt of RT and MAC remained significantly associated with improved OS (HR: 0.76; P < .001; and HR: 0.73; P < .001, respectively). MVA for receipt of surgery showed that MAC is a significant predictor for receiving surgery (odds ratio: 1.29; P = .009).ConclusionsOur results build on a growing literature supporting RT and MAC in treating LAPC. Additionally, we believe that-in the absence of prospective data-this makes a strong case for considering MAC with RT at ACs and HVFs for treating LAPC

Treatment strategies and clinical outcomes of locally advanced pancreatic cancer patients treated at high-volume facilities and academic centers

Purpose: Locally advanced pancreatic cancer (LAPC) treatment has varying practice patterns with poor outcomes. We investigated treatment using single-agent chemotherapy and multiagent chemotherapy (MAC) with or without radiation therapy (RT) at high-volume facilities (HVFs) and academic centers (ACs). Methods and Materials: The National Cancer Database was used to obtain data on 10,139 patients with LAPC. HVF was defined as the top 5% of facilities per number of patients treated at each facility. Univariate and multivariable (MVA) analysis Cox regressions were performed to identify the impact of HVF, AC, MAC, and RT on overall survival (OS). Results: The median age of patients was 66 years (range, 22-90); 50.1% were male and 49.9% female. Of the patients, 46.1% received MAC, 53.8% received single-agent chemotherapy, 45.7% received RT, 54.3% did not receive RT, and 5% underwent surgical resection. The median follow-up was 48.8 months. On MVA, treatment at HVFs and ACs remained significantly associated with improved OS, with a hazard ratio (HR) of 0.84 (P < .001) and 0.94 (P = .004), respectively. The median OS for HVF treatment compared with low-volume facilities was 14.3 versus 11.2 months, respectively (P < .001). The median OS for AC treatment versus non-AC was 12.1 versus 10.8 months, respectively (P < .001). Additionally, on MVA, receipt of RT and MAC remained significantly associated with improved OS (HR: 0.76; P < .001; and HR: 0.73; P < .001, respectively). MVA for receipt of surgery showed that MAC is a significant predictor for receiving surgery (odds ratio: 1.29; P = .009). Conclusions: Our results build on a growing literature supporting RT and MAC in treating LAPC. Additionally, we believe that—in the absence of prospective data—this makes a strong case for considering MAC with RT at ACs and HVFs for treating LAPC

Palliative Radiation Therapy for Bone Metastases in Neuroendocrine Neoplasms.

PurposeBone metastases are reported in 10% to 12% of patients with neuroendocrine neoplasms (NENs) and can lead to pain and skeletal-related events (SREs), resulting in diminished quality of life and functional status. In other solid tumors with bone metastases, radiation therapy (RT) is an established treatment approach for SREs, yet few data are available in NENs historically considered to be radioresistant. We hypothesize that RT is effective for pain and other SREs in NENs and aimed to delineate any differences in pain palliation and time until progression of pain between different fractionation and dosing schedules of RT.Methods and materialsWe retrospectively reviewed 686 records of patients with NENs treated at the institution between 2011 and 2018 and identified 28 (4.1%) patients treated with RT for 61 cases of SREs. The primary endpoint was change in patient reported pain scores after RT.ResultsAll 28 patients experienced bone pain. Nineteen sites were treated with a single fraction (doses of 800-1800&nbsp;cGy) and 42 sites with fractionated regimens (doses of 900-3750&nbsp;cGy over 3-15 fractions). In 55 of 61 cases (90%), patients experienced improvement in pain after RT. The median time to recurrence or progression of pain was 3.5&nbsp;months. Significant differences were found between primary site and change in performance status (P&nbsp;=&nbsp;.024), sex, and reported magnitude of pain score decrease after RT (P&nbsp;=&nbsp;.025). There were no differences in the time to the progression of pain, change in performance status, and degree of improvement in pain based on age, chemotherapy received during RT, or radiation site. Outcomes were similar for patients who received single-fraction versus fractionated regimens (P&nbsp;=&nbsp;.545) and between those receiving palliative versus ablative RT regimens (P&nbsp;=&nbsp;.812).ConclusionsAlthough the majority of cases in this NEN cohort benefited from RT, additional studies on the use of RT in the treatment of painful bone metastases are warranted

Multiplatform profiling of pancreatic neuroendocrine tumors: Correlative analyses of clinicopathologic factors and identification of co-occurring pathogenic alterations.

BackgroundMulti-omic profiling of pancreatic neuroendocrine tumors (PanNETs) was performed to correlate genomic, proteomic, and molecular pathway alterations with clinicopathologic factors and identify novel co-occurring pathogenic alterations of potential clinical relevance to PanNET management.MethodsPanNETs referred to Perthera, Inc. having undergone molecular profiling for precision matched therapeutic purposes were screened. Correlative analyses were performed using Fisher's exact test across individual pathogenic alterations or altered molecular pathways and clinicopathologic variables. Associations were visualized by hierarchical clustering. Prognostic associations with overall survival (OS) were identified using Cox regression for pathogenic alterations and pathway-level alterations. Hazard ratios (HR) and odds ratios (OR) were reported with 95% confidence intervals (CI).ResultsFrom 12/2014-1/2019, 46 patients with predominantly locally advanced and metastatic PanNETs were included. MEN1 alterations by next-generation sequencing (NGS) were less associated with having high-grade PanNETs and metastatic disease at diagnosis (p ≤ 0.05). Genomic alterations associated with increased replicative stress (primarily driven by RB1 and TP53) correlated with higher grade (OR 6.87 [95% CI: 1.57-35.18], p = 0.0043) and worse OS (HR 13.62 [95% CI: 1.51-122.5], p = 0.0198). Other significant associations included: ERCC1 protein expression with DAXX or MEN1 alterations (NGS), PTEN (NGS) with ARID1A or TP53 alterations (NGS), and history of diabetes coincided with cell cycle pathway alterations but was mutually exclusive with replicative stress pathway alterations.ConclusionsWe identified several molecular signatures of potential clinical significance for therapeutic targeting and prognostication in PanNETs warranting prospective validation. Our findings are hypothesis generating and can inform larger molecular profiling efforts in PanNETs

Hyaluronan heterogeneity in pancreatic ductal adenocarcinoma: Primary tumors compared to sites of metastasis.

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with poor survival. The dense desmoplastic stroma in PDAC contributes to treatment resistance. Among the components comprising the tumor stroma, hyaluronan (HA) has been demonstrated to play a critical role in tumor progression and survival. Previous preliminary studies have suggested differences in HA expression in primary and metastatic foci of PDAC. However, the effects of treatment and location of HA expression as a biomarker signature remain unknown; this study sought to compare HA expression in primary and metastatic sites of PDAC.MethodsTissue from primary and metastatic PDACs were obtained from Cedars-Sinai Medical Center along with associated clinical data. Tissue slides were stained for H&amp;E, HA, and CD44. Associations between HA levels and the evaluated variables were examined including progression free survival and overall survival.ResultsHA score was significantly higher in primary PDACs compared to sites of metastases (p&nbsp;=&nbsp;0.0148). Within the metastases, HA score was significantly higher in liver metastases compared to metastases at other sites (p&nbsp;=&nbsp;0.0478). In the treatment-naive liver metastasis cohort, patients with HA high status had decreased progression free survival and overall survival compared to patients with HA low status (p&nbsp;=&nbsp;0.0032 and p&nbsp;=&nbsp;0.0478, respectively).ConclusionsHA score is variable between primary PDAC, PDAC metastatic to the liver, and PDAC metastatic to other sites. Within liver metastases, patients with HA high status had decreased progression free survival and overall survival compared to patients with HA low status. HA levels can serve as a potential biomarker to guide pancreatic cancer treatments and trial design for agents targeting the stroma

Cancer epithelia-derived mitochondrial DNA is a targetable initiator of a paracrine signaling loop that confers taxane resistance.

Stromal-epithelial interactions dictate cancer progression and therapeutic response. Prostate cancer (PCa) cells were identified to secrete greater concentration of mitochondrial DNA (mtDNA) compared to noncancer epithelia. Based on the recognized coevolution of cancer-associated fibroblasts (CAF) with tumor progression, we tested the role of cancer-derived mtDNA in a mechanism of paracrine signaling. We found that prostatic CAF expressed DEC205, which was not expressed by normal tissue-associated fibroblasts. DEC205 is a transmembrane protein that bound mtDNA and contributed to pattern recognition by Toll-like receptor 9 (TLR9). Complement C3 was the dominant gene targeted by TLR9-induced NF-κB signaling in CAF. The subsequent maturation complement C3 maturation to anaphylatoxin C3a was dependent on PCa epithelial inhibition of catalase in CAF. In a syngeneic tissue recombination model of PCa and associated fibroblast, the antagonism of the C3a receptor and the fibroblastic knockout of TLR9 similarly resulted in immune suppression with a significant reduction in tumor progression, compared to saline-treated tumors associated with wild-type prostatic fibroblasts. Interestingly, docetaxel, a common therapy for advanced PCa, further promoted mtDNA secretion in cultured epithelia, mice, and PCa patients. The antiapoptotic signaling downstream of anaphylatoxin C3a signaling in tumor cells contributed to docetaxel resistance. The inhibition of C3a receptor sensitized PCa epithelia to docetaxel in a synergistic manner. Tumor models of human PCa epithelia with CAF expanded similarly in mice in the presence or absence of docetaxel. The combination therapy of docetaxel and C3 receptor antagonist disrupted the mtDNA/C3a paracrine loop and restored docetaxel sensitivity

Tumor hyaluronan as a novel biomarker in non-small cell lung cancer: A retrospective study

IntroductionHyaluronan (HA) accumulation is associated with tumorigenesis and aggressive tumor behavior.AimsWe investigated the biomarker potential of HA in non-small cell lung cancer (NSCLC).MethodsHA levels were scored using affinity histochemistry in 137 NSCLC samples stratified by HA score ≤10, 11-20, 21-30, and &gt;30 with HA-high defined as ≥25% expression in the extracellular matrix (ECM) of the tumor surface area. Overall survival (OS) and time to progression from initiation of taxane therapy (TTP) were compared using log-rank tests based on HA score.ResultsOf 122 patients with recurrent/metastatic NSCLC, 93 had mean HA scores that were not significantly different across clinicopathologic variables. Frequency of HA-high tumors did not differ by histology (34/68 adenocarcinomas vs. 12/25 squamous tumors, Fisher's p = 1.0000). Median OS for recurrent/metastatic adenocarcinoma was 35.5 months (95%, 23.6-50.3) vs. 17.9 months for squamous (95%, 12.7-37.0, log-rank test, p = 0.0165). OS was not significantly different by HA quartiles, high or low (&lt;25) HA score and tumor histology, and HA biopsy site (all p &gt; 0.05). Median TTP (n = 98) significantly differed by HA quartile (2.8 months for HA score ≤10; 5.0 months for 11-20; 7.9 months for 21-30; 3.9 months for &gt;30, p = 0.0265). Improved TTP trended in HA-high over HA-low tumors (n = 98, p = 0.0911).ConclusionIn this NSCLC cohort, tumor HA level represents a potential biomarker for TTP, which remains a cornerstone of NSCLC therapy. Further validation is warranted to identify the HA accumulation threshold associated with clinical benefit

Feasibility and efficacy of enteral tube feeding on weight stability, lean body mass, and patient-reported outcomes in pancreatic cancer cachexia.

BackgroundAdvanced pancreatic ductal adenocarcinoma (PDAC) is characterized by progressive weight loss and nutritional deterioration. This wasting has been linked to poor survival outcomes, alterations in host defenses, decreased functional ability, and diminished health-related quality of life (HRQOL) in pancreatic cancer patients. There are currently no standardized approaches to the management of pancreatic cancer cachexia. This study explores the feasibility and efficacy of enteral tube feeding of a peptide-based formula to improve weight stability and patient-reported outcomes (PROs) in advanced PDAC patients with cachexia.MethodsThis was a single-institution, single-arm prospective trial conducted between April 2015 and March 2019. Eligible patients were adults (&gt;18&nbsp;years) diagnosed with advanced or locally advanced PDAC and cachexia, defined as greater than 5% unexplained weight loss within 6&nbsp;months from screening. The study intervention included three 28&nbsp;day cycles of a semi-elemental peptide-based formula, administered through a jejunal or gastrojejunal feeding tube. The primary outcome was weight stability at 3&nbsp;months (Cycle 3), defined as weight change less than 0.1&nbsp;kg/baseline BMI unit from baseline. Secondary outcomes included changes in lean body mass, appendicular lean mass, bone mineral density, fat mass, and percent body fat, as measured with a DEXA scan, HRQOL (EORTC QLQC30) and NIH PROMIS PROs assessed at each cycle. Daily activity (steps, distance, active minutes, heart rate, and sleep) were remotely monitored using a wearable activity monitor (Fitbit) over the 3&nbsp;month study period.ResultsThirty-six patients were screened for eligibility, 31 patients consented onto study and underwent jejunal tube placement, and 16 patients completed treatment: mean age 67&nbsp;years (SD 9.3), 43.8% male. Among evaluable patients (n&nbsp;=&nbsp;16), weight stability was achieved in 10 patients (62.5%), thus completing the trial early. Increases in lean body mass (1273.1, SD: 4078, P&nbsp;=&nbsp;0.01) and appendicular lean mass (0.45, SD: 0.6, P&nbsp;=&nbsp;0.02) were observed. Statistically significant improvements at Cycle 3 from baseline were also observed for QLQC30 role function [mean difference (MD): 20.1, P&nbsp;=&nbsp;0.03], appetite (MD: 27.4, P&nbsp;=&nbsp;0.02), and global health scores (MD: 13.3, P&nbsp;=&nbsp;0.05) as well as for NIH PROMIS t-scores for depression (MD: -10.4, P&nbsp;=&nbsp;0.006) and pain interference (MD: -7.5, P&nbsp;=&nbsp;0.05). Objectively monitored (Fitbit) activity levels increased, although statistical significance was not reached.ConclusionsOur findings suggest that enteral nutrition support may improve weight stability, lean body mass, appendicular lean mass and PROs in PDAC patients with cachexia who completed treatment, representing a subsample of the study population. The feasibility and role of enteral feeding in routine care remain unclear, and larger and randomized controlled trials are warranted