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.
There is growing interest in identifying predictive biomarkers for inhibitors of programmed cell death protein 1 receptor (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T-lymphocyte ...associated protein 4 (CTLA-4). Given the links between the stool microbiota, anticancer immunosurveillance, and general health, the composition of the gut microbiome has recently undergone investigation as a biomarker for immunotherapy. In this review, we highlight published results from preclinical and clinical studies to date supporting a relationship between the gut microbiome and antitumor efficacy of immune checkpoint inhibitors. Despite the promising and hypothesis-generating findings that have been produced in this arena to date, there remain some inconsistencies amongst present data that may need to be resolved to contribute to further development. Among these, a better understanding of the immunomodulatory function of the microbiome, standardization in sampling, sequencing techniques, and data analysis, and ensuring uniformity across various aspects of study design are warranted in conducting future prospective studies seeking to validate the gut microbiome as a potential biomarker of response to checkpoint blockade.
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.
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.
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.
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.
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.
Display omitted
Neil Bhowmick and colleagues found that targeting CD105 with carotuximab, inhibiting bone morphogenic protein signaling, affected a recognized hormone therapy resistance. Combining carotuximab with hormone therapy limited tumor progression in mouse models as well as supporting progression-free survival of patients determined to be resistant to hormone therapy alone.
Plasminogen activator inhibitor-1 (PAI-1) has a pro-tumorigenic function via its pro-angiogenic and anti-apoptotic activities. Here, we demonstrate that PAI-1 promotes the recruitment and M2 ...polarization of monocytes/macrophages through different structural domains. Its LRP1 interacting domain regulated macrophage migration, while its C-terminal uPA interacting domain promoted M2 macrophage polarization through activation of p38MAPK and nuclear factor κB (NF-κB) and induction of an autocrine interleukin (IL)-6/STAT3 activation pathway. We then show in several experiments in mice that expression of PAI-1 is associated with increased tumorigenicity, increased presence of M2 macrophages, higher levels of IL-6, and increased STAT3 phosphorylation in macrophages. Strong positive correlations between PAI-1, IL-6, and CD163 (M2 marker) expression were also found by meta-analysis of transcriptome data in many human cancers. Altogether, these data provide evidence for a mechanism explaining the paradoxical pro-tumorigenic function of PAI-1 in cancer.
Display omitted
•PAI-1 promotes monocyte migration via its N-terminal LRP binding domain•PAI-1 promotes M2 macrophage polarization via its C-terminal uPA interacting domain•The action on macrophage polarization is via an IL-6/STAT3 autocrine loop
The serine protease inhibitor plasminogen activator inhibitor-1 (PAI-1) has a paradoxical pro-angiogenic and protective effect on cancer cells. Kubala et al. provide evidence for a third pro-tumorigenic function by demonstrating that PAI-1 promotes recruitment and polarization toward a pro-tumorigenic phenotype of tumor-associated macrophages.
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.
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.
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).
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.
PDF
