Antagonizing CD105 and androgen receptor to target stromal-epithelial interactions for clinical benefit.

Androgen receptor signaling inhibitors (ARSIs) are standard of care for advanced prostate cancer (PCa) patients. Eventual resistance to ARSIs can include the expression of androgen receptor (AR) splice variant, AR-V7, expression as a recognized means of ligand-independent androgen signaling. We demonstrated that interleukin (IL)-6-mediated AR-V7 expression requires bone morphogenic protein (BMP) and CD105 receptor activity in both PCa and associated fibroblasts. Chromatin immunoprecipitation supported CD105-dependent ID1- and E2F-mediated expression of RBM38. Further, RNA immune precipitation demonstrated RBM38 binds the AR-cryptic exon 3 to enable AR-V7 generation. The forced expression of AR-V7 by primary prostatic fibroblasts diminished PCa sensitivity to ARSI. Conversely, downregulation of AR-V7 expression in cancer epithelia and associated fibroblasts was achieved by a CD105-neutralizing antibody, carotuximab. These compelling pre-clinical findings initiated an interventional study in PCa patients developing ARSI resistance. The combination of carotuximab and ARSI (i.e., enzalutamide or abiraterone) provided disease stabilization in four of nine assessable ARSI-refractory patients. Circulating tumor cell evaluation showed AR-V7 downregulation in the responsive subjects on combination treatment and revealed a three-gene panel that was predictive of response. The systemic antagonism of BMP/CD105 signaling can support ARSI re-sensitization in pre-clinical models and subjects that have otherwise developed resistance due to AR-V7 expression.

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

INTRODUCTION: Hyaluronan (HA) accumulation is associated with tumorigenesis and aggressive tumor behavior. AIMS: We investigated the biomarker potential of HA in non-small cell lung cancer (NSCLC). METHODS: HA levels were scored using affinity histochemistry in 137 NSCLC samples stratified by HA score ≤10, 11-20, 21-30, and >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. RESULTS: Of 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 (<25) HA score and tumor histology, and HA biopsy site (all p > 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 >30, p = 0.0265). Improved TTP trended in HA-high over HA-low tumors (n = 98, p = 0.0911). CONCLUSION: In 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.

Exceptional Response to Erdafitinib in FGFR2-Mutated Metastatic Pancreatic Ductal Adenocarcinoma.

Despite advances in cancer therapeutics, pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest malignancies, with a poor prognosis at time of diagnosis. Research in PDAC has suggested that adaptive signaling in the tumor microenvironment may promote tumor proliferation and survival. Several FGFR fusion genes-specifically FGFR2-are involved with the creation and progression of cancer. These mutations are found in a variety of cancer types. This report presents a unique case of a young patient with stage IV PDAC with a known FGFR2 fusion. This molecular alteration afforded a remarkable response to FGFR inhibitor therapy, erdafitinib, after the patient experienced disease progression on multiple chemotherapy regimens.

Chemotherapy predictors and a time-dependent chemotherapy effect in metastatic esophageal cancer.

BACKGROUND: Chemotherapy has long been shown to confer a survival benefit in patients with metastatic esophageal cancer. However, not all patients with metastatic disease receive chemotherapy. AIM: To evaluate a large cancer database of metastatic esophageal cancer cases to identify predictors of receipt to chemotherapy and survival. METHODS: We interrogated the National Cancer Database (NCDB) between 2004-2015 and included patients with M1 disease who had received or did not receive chemotherapy. A logistic regression model was used to examine the associations between chemotherapy and potential confounders and a Cox proportional hazards model was employed to examine the effect of chemotherapy on overall survival (OS). Propensity score analyses were further performed to balance measurable confounders between patients treated with and without chemotherapy. RESULTS: A total of 29182 patients met criteria for inclusion in this analysis, with 21911 (75%) receiving chemotherapy and 7271 (25%) not receiving chemotherapy. The median follow-up was 69.45 mo. The median OS for patients receiving chemotherapy was 9.53 mo (9.33-9.72) vs 2.43 mo (2.27-2.60) with no chemotherapy. Year of diagnosis 2010-2014 [odds ratio (OR): 1.29, 95% confidence interval (CI): 1.17-1.43, P value < 0.001], median income > $46000 (OR: 1.49, 95%CI: 1.27-1.75, P value < 0.001), and node-positivity (OR: 1.35, 95%CI: 1.20-1.52, P < 0.001) were independent predictors of receiving chemotherapy, while female gender (OR: 0.86, 95%CI: 0.76-0.98, P = 0.019), black race (OR: 0.76, 95%CI: 0.67-0.93, P = 0.005), uninsured status (OR: 0.41, 95%CI: 0.33-0.52, P < 0.001), and high Charlson Comorbidity Index (CCI) (OR for CCI ≥ 2: 0.61, 95%CI: 0.50-0.74, P < 0.001) predicted for lower odds of receiving chemotherapy. Modeling the effect of chemotherapy on OS using a time-dependent coefficient showed that chemotherapy was associated with improved OS up to 10 mo, after which there is no significant effect on OS. Moreover, uninsured status [hazard ratio (HR): 1.20, 95%CI: 1.09-1.31, P < 0.001], being from the geographic Midwest (HR: 1.07, 95%CI: 1.01-1.14, P = 0.032), high CCI (HR for CCI ≥ 2: 1.16, 95%CI: 1.07-1.26, P < 0.001), and higher tumor grade (HR for grade 3 vs grade 1: 1.28, 95%CI: 1.14-1.44, P < 0.001) and higher T stage (HR for T1 vs T4: 0.89, 95%CI: 0.84-0.95, P < 0.001) were independent predictors of worse OS on multivariable analyses. CONCLUSION: In this large, retrospective NCDB analysis, we identified several socioeconomic and clinicopathologic predictors for receiving chemotherapy and OS in patients with metastatic esophageal cancer. The benefit of chemotherapy on OS is time-dependent and favors early initiation. Focused outreach in lower income and underinsured patients is critical as receipt of chemotherapy is associated with improved OS.

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

BACKGROUND: Pancreatic 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. METHODS: Tissue from primary and metastatic PDACs were obtained from Cedars-Sinai Medical Center along with associated clinical data. Tissue slides were stained for H&E, HA, and CD44. Associations between HA levels and the evaluated variables were examined including progression free survival and overall survival. RESULTS: HA score was significantly higher in primary PDACs compared to sites of metastases (p = 0.0148). Within the metastases, HA score was significantly higher in liver metastases compared to metastases at other sites (p = 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 = 0.0032 and p = 0.0478, respectively). CONCLUSIONS: HA 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.

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

BACKGROUND: Advanced 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. METHODS: This was a single-institution, single-arm prospective trial conducted between April 2015 and March 2019. Eligible patients were adults (>18 years) diagnosed with advanced or locally advanced PDAC and cachexia, defined as greater than 5% unexplained weight loss within 6 months from screening. The study intervention included three 28 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 months (Cycle 3), defined as weight change less than 0.1 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 month study period. RESULTS: Thirty-six patients were screened for eligibility, 31 patients consented onto study and underwent jejunal tube placement, and 16 patients completed treatment: mean age 67 years (SD 9.3), 43.8% male. Among evaluable patients (n = 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 = 0.01) and appendicular lean mass (0.45, SD: 0.6, P = 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 = 0.03], appetite (MD: 27.4, P = 0.02), and global health scores (MD: 13.3, P = 0.05) as well as for NIH PROMIS t-scores for depression (MD: -10.4, P = 0.006) and pain interference (MD: -7.5, P = 0.05). Objectively monitored (Fitbit) activity levels increased, although statistical significance was not reached. CONCLUSIONS: Our 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.

Impact of palliative therapies in metastatic esophageal cancer patients not receiving chemotherapy.

BACKGROUND: Palliative therapy has been associated with improved overall survival (OS) in several tumor types. Not all patients with metastatic esophageal cancer receive palliative chemotherapy, and the roles of other palliative therapies in these patients are limited. AIM: To investigate the impact of other palliative therapies in patients with metastatic esophageal cancer not receiving chemotherapy. METHODS: The National Cancer Database was used to identify patients between 2004-2015. Patients with M1 disease who declined chemotherapy and had known palliative therapy status [palliative therapies were defined as surgery, radiotherapy (RT), pain management, or any combination thereof] were included. Cases with unknown chemotherapy, RT, or nonprimary surgery status were excluded. Kaplan-Meier estimates of OS were calculated. Cox proportional hazards regression models were employed to examine factors influencing survival. RESULTS: Among 140234 esophageal cancer cases, we identified 1493 patients who did not receive chemotherapy and had complete data. Median age was 70 years, most (66.3%) had a Charlson Comorbidity Index (CCI) of 0, and 37.1% were treated at an academic center. The majority (72.7%) did not receive other palliative therapies. On both univariate and multivariable analyses, there was no difference in OS between those receiving other palliative therapy (median 2.83 mo, 95%CI: 2.53-3.12) vs no palliative therapy (2.37 no, 95%CI: 2.2-2.56; multivariable P = 0.290). On univariate, but not multivariable analysis, treatment at an academic center was predictive of improved OS [Hazard ratio (HR) 0.90, 95%CI: 0.80-1.00; P = 0.047]. On multivariable analysis, female sex (HR 0.81, 95%CI: 0.71-0.92) and non-black, other race compared to white race (HR 0.72, 95%CI: 0.56-0.93) were associated with reduced mortality, while South geographic region relative to West region (HR 1.23, 95%CI: 1.04-1.46) and CCI of 1 relative to CCI of 0 (HR 1.17, 95%CI: 1.03-1.32) were associated with increased mortality. Higher histologic grade and T-stage were also associated with worse OS (P < 0.05). CONCLUSION: Palliative therapies other than chemotherapy conferred a numerically higher, but not statistically significant difference in OS among patients with metastatic esophageal cancer not receiving chemotherapy. Quality of life metrics, inpatient status, and subgroup analyses are important for examining the role of palliative therapies other than chemotherapy in metastatic esophageal cancer and future studies are warranted.

Priority Rankings of Patient-Reported Outcomes for Pancreatic Ductal Adenocarcinoma: A Comparison of Patient and Physician Perspectives.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is associated with high symptom burden. However, treatment decisions currently depend heavily on physician interpretation of clinical parameters and may not consider patients' health preferences. The NIH Patient-Reported Outcomes Measurement Information System (PROMIS) initiative standardized a set of patient-reported outcomes for use in chronic diseases. This study identifies preference rankings among patients with PDAC and physicians for PROMIS domains and compares the priorities of patients and their providers. METHODS: We condensed the 96 NIH PROMIS adult domains into 31 domains and created a Maximum Difference Scaling questionnaire. Domain preference scores were generated from the responses of patients with PDAC and physicians, which were compared using Maximum Difference Scaling software across demographic and clinical variables. RESULTS: Participants included 135 patients with PDAC (53% male; median age, 68 years) and 54 physicians (76% male; median years of experience, 10). Patients selected physical functioning (PF) as their top priority, whereas physicians identified pain as most important. PF, ability to perform activities of daily living, and symptom management were within the top 5 domains for both patients and physicians, and varied only slightly across age, sex, and ethnicity. However, several domains were ranked significantly higher by patients than by physicians, including but not limited to PF; ability to do things for yourself, family, and friends; ability to interact with others to obtain help; and sleep quality. Physicians ranked pain, anxiety, and depression higher than patients did. CONCLUSIONS: Our findings suggest that patients with PDAC value PF and engaging in daily and social activities the most, whereas physicians prioritize symptoms such as pain. Patient-reported outcomes need to become more integrated into PDAC care and research to better identify unmet patient needs, inform treatment decisions, and develop therapies that address outcomes valued by patients.

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.

Soluble CD105 is prognostic of disease recurrence in prostate cancer patients.

While the overall 5-year survival rate for prostate cancer is near 100%, up to 35% of patients will develop recurrent disease. At the time of prostatectomy, prostate-specific antigen (PSA) is used to guide primary therapy with the goal of curative intervention. It can be valuable to know when primary therapy may not in fact be curative, so that subsequent adjuvant therapy can be administered at an early stage to limit progression. We examined prostate cancer patients with PSA ≤10 ng/mL that were all subjected to prostatectomy with at least 5 years of follow-up (n = 181). Based on data that endoglin (CD105) signaling in the tumor can contribute to prostate cancer progression, we examined the expression of soluble CD105 (sCD105) in the patient plasma. To determine the relation of plasma sCD105 measures to cellular CD105 in tissues, we tested an independent set of prostate cancer tissues and paired plasma (n = 31). Elevated sCD105 was found to be associated with recurrence-free survival of prostate cancer patients. Further, sCD105 levels in patient plasma were inversely correlated with cellular CD105 expression. This translational study supported preclinical data demonstrating the pro-tumorigenic capacity of cellular CD105 and provide a blood-based biomarker, sCD105, for prostate cancer recurrence in prostatectomy patients with PSA levels ≤10 ng/mL.

Palliative Radiation Therapy for Bone Metastases in Neuroendocrine Neoplasms.

PURPOSE: Bone 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 MATERIALS: We 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. RESULTS: All 28 patients experienced bone pain. Nineteen sites were treated with a single fraction (doses of 800-1800 cGy) and 42 sites with fractionated regimens (doses of 900-3750 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 months. Significant differences were found between primary site and change in performance status (P = .024), sex, and reported magnitude of pain score decrease after RT (P = .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 = .545) and between those receiving palliative versus ablative RT regimens (P = .812). CONCLUSIONS: Although 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.

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.

3D Co-culture System of Mouse Prostatic Wild-type Fibroblasts withHuman Prostate Cancer Epithelial Cells.

Heterogeneous prostatic carcinoma-associated fibroblasts (CAF) contribute to tumor progression. This was established using transgenic mouse models. Paracrine interactions between fibroblasts and epithelial cells were further interrogated using isolated 2D cell culture systems, but 3D culture systems currently being developed can better mimic reciprocal interactions potentially found in the native tissue. To understand paracrine and juxtacrine signaling among fibroblasts and epithelia, 3D co-cultures with species differences allows for further subsequent analysis of the cultures. The use of mouse and human cells, for example, in one system allows for species-specific FACS or quantitative PCR analysis. This protocol describes the use of a 3D Co-culture System of Mouse Prostatic Wild-type Fibroblasts with Human Prostate Cancer Epithelial Cells.

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.