Validation of SFRP1 Promoter Hypermethylation in Plasma as a Prognostic Marker for Survival and Gemcitabine Effectiveness in Patients with Stage IV Pancreatic Adenocarcinoma

Stubbe, Benjamin Emil; Henriksen, Stine Dam; Madsen, Poul Thøis; Larsen, Anders Christian; Krarup, Henrik; Pedersen, Inge Søkilde; Johansen, Martin Berg; Thorlacius-Ussing, Ole

doi:10.3390/cancers13225717

Cited by 9 publications

(5 citation statements)

References 44 publications

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“…Still, Sotorasib is considered a breakthrough in KRAS-dependent cancer therapy. Both of the C2TSG proteins presented above, i.e., SFRP1 and ITIH5, are also downregulated due to promoter hypermethylation in pancreatic cancer (our unpublished data) and recent studies in an animal model for metastasis (ITIH5) [ 43 ] and a clinical model for drug response (SFRP1) [ 72 ] have indicated the importance of these C2TSG proteins in suppressing pancreatic cancer progression.…”

Section: Discussionmentioning

confidence: 85%

White Paper: Mimetics of Class 2 Tumor Suppressor Proteins as Novel Drug Candidates for Personalized Cancer Therapy

Dahl

Villwock

Habenberger

et al. 2022

Cancers

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The aim of our proposed concept is to find new target structures for combating cancers with unmet medical needs. This, unfortunately, still applies to the majority of the clinically most relevant tumor entities such as, for example, liver cancer, pancreatic cancer, and many others. Current target structures almost all belong to the class of oncogenic proteins caused by tumor-specific genetic alterations, such as activating mutations, gene fusions, or gene amplifications, often referred to as cancer “driver alterations” or just “drivers.” However, restoring the lost function of tumor suppressor genes (TSGs) could also be a valid approach to treating cancer. TSG-derived proteins are usually considered as control systems of cells against oncogenic properties; thus, they represent the brakes in the “car-of-life.” Restoring these tumor-defective brakes by gene therapy has not been successful so far, with a few exceptions. It can be assumed that most TSGs are not being inactivated by genetic alteration (class 1 TSGs) but rather by epigenetic silencing (class 2 TSGs or short “C2TSGs”). Reactivation of C2TSGs in cancer therapy is being addressed by the use of DNA demethylating agents and histone deacetylase inhibitors which act on the whole cancer cell genome. These epigenetic therapies have neither been particularly successful, probably because they are “shotgun” approaches that, although acting on C2TSGs, may also reactivate epigenetically silenced oncogenic sequences in the genome. Thus, new strategies are needed to exploit the therapeutic potential of C2TSGs, which have also been named DNA methylation cancer driver genes or “DNAme drivers” recently. Here we present a concept for a new translational and therapeutic approach that focuses on the phenotypic imitation (“mimesis”) of proteins encoded by highly disease-relevant C2TSGs/DNAme drivers. Molecular knowledge on C2TSGs is used in two complementary approaches having the translational concept of defining mimetic drugs in common: First, a concept is presented how truncated and/or genetically engineered C2TSG proteins, consisting solely of domains with defined tumor suppressive function can be developed as biologicals. Second, a method is described for identifying small molecules that can mimic the effect of the C2TSG protein lost in the cancer cell. Both approaches should open up a new, previously untapped discovery space for anticancer drugs.

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Section: Discussionmentioning

confidence: 85%

White Paper: Mimetics of Class 2 Tumor Suppressor Proteins as Novel Drug Candidates for Personalized Cancer Therapy

Dahl

Villwock

Habenberger

et al. 2022

Cancers

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“…TFPI2 (Tissue Factor Pathway Inhibitor 2) is a Kunitz-type serine proteinase inhibitor [ 28 ], which prevents the degradation of the extracellular matrix [ 29 ] and whose epigenetic inactivation contributes to the proliferation and invasiveness of tumors such as PDAC [ 30 ]. SFRP1 (Secreted Frizzled Related Protein 1) acts as a modulator of the Wnt pathway, and its hypermethylation has been associated with increased aggressiveness and decreased sensitivity to gemcitabine treatment in PDAC [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Circulating NPTX2 methylation as a non-invasive biomarker for prognosis and monitoring of metastatic pancreatic cancer

García-Ortiz,

Cano-Ramírez,

Toledano-Fonseca

et al. 2023

Clin Epigenet

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Background Pancreatic cancer is the most lethal cancer with a dismal prognosis mainly due to diagnosis at advanced stage and ineffective treatments. CA19-9 levels and computed tomography (CT) imaging are the main standard criteria for evaluating disease progression and treatment response. In this study we explored liquid biopsy-based epigenetic biomarkers for prognosis and monitoring disease in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Methods Plasma samples were collected from 44 mPDAC patients at the time of diagnosis, and in 15 of them, additional samples were obtained during follow-up of the disease. After cell-free DNA (cfDNA), isolation circulating levels of methylated NPTX2, SPARC, BMP3, SFRP1 and TFPI2 genes were measured using digital droplet PCR (ddPCR). BEAMing technique was performed for quantitation of RAS mutations in cfDNA, and CA19-9 was measured using standard techniques. Results NPTX2 was the most highly and frequently methylated gene in cfDNA samples from mPDAC patients. Higher circulating NPTX2 methylation levels at diagnosis were associated with poor prognosis and efficiently stratified patients for prediction of overall survival (6.06% cut-off, p = 0.0067). Dynamics of circulating NPTX2 methylation levels correlated with disease progression and response to therapy and predicted better than CA19-9 the evolution of disease in mPDAC patients. Remarkably, in many cases the disease progression detected by CT scan was anticipated by an increase in circulating NPTX2 methylation levels. Conclusions Our study supports circulating NPTX2 methylation levels as a promising liquid biopsy-based clinical tool for non-invasive prognosis, monitoring disease evolution and response to treatment in mPDAC patients.

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“…Although no large-scale prospective studies have been published, liquid biopsies using blood samples as sources of tumor-derived genetic material may prove useful for prediction of prognosis and early assessment of treatment response in PC [46]. Among other candidate measures, a prior study suggested that promotor hypermethylation (ph) of secreted frizzled-related protein 1 (SFRP1) in plasma cell free DNA may be a prognostic marker in Gem-treated PC patients [47]. In the present study the prognostic and predictive value of ctDNA assessments will be investigated.…”

Section: Blood Biomarkersmentioning

confidence: 99%

A randomized phase II study of full dose gemcitabine versus reduced dose gemcitabine and nab-paclitaxel in vulnerable patients with non-resectable pancreatic cancer (DPCG-01)

Rasmussen,

Winther,

Chen

et al. 2023

Preprint

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Background According to current evidence, the best treatment for fit patients with non-resectable pancreatic cancer (PC) is combination chemotherapy, whereas frail patients are recommended gemcitabine (Gem) monotherapy. Randomized controlled trials in colorectal cancer and a post-hoc analysis of gemcitabine and nab-paclitaxel (GemNab) in PC suggest, however, that reduced dose of combination chemotherapy may be feasible and more efficient compared to monotherapy in frail patients. The aim of this study is to investigate whether reduced dose GemNab is superior to full dose Gem in patients with resectable PC, who are not candidates for full dose combination chemotherapy in first line. Methods The Danish Pancreas Cancer Group (DPCG)-01 trial is a national multicenter prospective randomized phase II trial. A total of 100 patients in ECOG performance status 0-2 with non-resectable PC, not candidate for full dose combination chemotherapy in first line, but eligible for full dose Gem, will be included. Patients are randomized 1:1 to either full dose Gem or GemNab in 80% of recommended dose. The primary endpoint is progression-free survival. Secondary endpoints are overall survival, overall response rate, quality of life, toxicity and rate of hospitalizations during treatment. The correlation between blood inflammatory markers, including YKL-40 and IL-6, circulating tumor DNA, and tissue biomarkers of resistance to chemotherapy and outcome will be explored. Finally, the study will include measures of frailty (G8, modified G8, and chair-stand-test) to assess whether scoring would enable a personalized allocation to different treatments or indicates a possibility for interventions. Discussion Single-drug treatment with Gem has for frail patients with non-resectable PC been the main treatment option for more than thirty years, but the impact on outcome is modest. If improved results and sustained tolerability with reduced dose combination chemotherapy can be shown, this could change the future practice for this increasing group of patients. Trial registration ClinicalTrials.gov Identifier: NCT05841420. Secondary Identifying No: N-20210068. EudraCT No: 2021-005067-52. Protocol version: 1.5, 16-MAY-2023.

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Validation of SFRP1 Promoter Hypermethylation in Plasma as a Prognostic Marker for Survival and Gemcitabine Effectiveness in Patients with Stage IV Pancreatic Adenocarcinoma

Cited by 9 publications

References 44 publications

White Paper: Mimetics of Class 2 Tumor Suppressor Proteins as Novel Drug Candidates for Personalized Cancer Therapy

White Paper: Mimetics of Class 2 Tumor Suppressor Proteins as Novel Drug Candidates for Personalized Cancer Therapy

Circulating NPTX2 methylation as a non-invasive biomarker for prognosis and monitoring of metastatic pancreatic cancer

A randomized phase II study of full dose gemcitabine versus reduced dose gemcitabine and nab-paclitaxel in vulnerable patients with non-resectable pancreatic cancer (DPCG-01)

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