Exploiting Heterogeneity in Hormone Therapy Response to Reveal Early Determinants of Drug Resistance in Advanced PCa
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- A) Density of tumor-infiltrating immune cells
研究概览
简要总结
The goal of this observational study is to study intra-patient tumor and TME heterogeneity after initiation of hormonal therapy (ADT +- ARSI), while the patient is responding to treatment, to understand the drivers of hormonal therapy resistance and identify potential novel therapeutic targets in metastatic prostate cancer patients. The main question it aims to answer if intra-tumor adaptive mechanisms including expression of immune checkpoint proteins and changes in the tumor immune infiltrate are related to the induction of a senescent phenotype in response to hormonal therapy.
Participants will asked to provide an FFPE and/or fresh biopsy sample from the primary tumor or a metastatic site at baseline (before starting hormonal therapy) and during the course of hormonal therapy. Additionally, a maximum of 2 blood tubes (10ml) will be collected each time.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Patients with histological diagnosis of advanced prostate cancer (defined as the presence of metastatic disease, including both metastatic hormone naïve prostate cancer patients and metastatic castration resistant prostate cancer patients);
- •Patients who started ADT or ADT plus AR inhibitor therapy (Enzalutamide, Darolutamide or Apalutamide or Abiraterone) in a standard therapy.
- •Have accessible metastatic and/or primitive disease to perform a biopsy safely during hormonal therapy (ADT or ADT plus AR inhibitor therapy) and before hormonal therapy (alternatively, as a basal biopsy could be used archival FFPE or frozen tumor material left over from surgical procedures or previous biopsies, if available)
- •Written acceptance of informed consent to be included in the present study.
- •Aged 18 or over.
- •Inclusion Criteria Group B:
- •Patients due for prostate biopsy to confirm the diagnosis of a prostate adenocarcinoma at high risk of metastatic disease. High risk is defined as follows:
- •PSA >=20ng/dL with or without imaging suggestive of metastatic prostate cancer OR
- •PSA >=10 ng/mL and <= 20 ng/mL AND >=33% risk to have a high grade disease on prostate biopsy according to the MSKCC nomogram "Risk of high grade cancer of prostate biopsy" (https://www.mskcc.org/nomograms/prostate/biopsy_risk_dynamic).
- •Written acceptance of informed consent to be included in the present study.
- •Aged 18 or over
排除标准
- 未提供
研究组 & 干预措施
Patients with histological diagnosis of advanced prostate cancer who started hormone therapy
A fresh tumor biopsies and FFPE block will be taken at baseline and after 4 weeks of hormone therapy and/or AR targeting agents. Blood samples for the isolation of plasma, serum and PBMC will be collected before the start of therapy and after 4 weeks of hormone therapy and/or AR targeting agents. The correlation of biopsies analyses and clinical data will advance the understanding of prostate cancer progression pathways and guide the design of subsequent studies in the field of personalized medicine.
干预措施: biopsy (Procedure)
Patients due for prostate biopsy to confirm the diagnosis of a prostate adenocarcinoma at high risk
A fresh tumor biopsies and FFPE block and blood samples for the isolation of plasma, serum and PBMC will be taken at baseline. This cohort was necessary because it is complex to intercept patients at the time they perform diagnostic biopsy and then obtain fresh biopsies pre-hormonal treatment. If patients of this group will metastasize, these patients will be incorpored in the other.
干预措施: Prostate biopsy (Procedure)
结局指标
主要结局
A) Density of tumor-infiltrating immune cells
时间窗: From enrollment to 24 months
Description: Density of tumor-infiltrating lymphocytes (CD3+, CD4+, CD8+, FOXP3+) assessed by multiplex immunohistochemistry in tumor biopsies from patients under hormonal therapy. Unit of Measure: Cells/mm²
Tumor expression of Immune checkpoints
时间窗: From enrollment to 24 months
The investigators will pursue IHC assessment of immunomodulatory proteins. I will use a multiplexed customized IHC panel and the expression of the immunomodulatory proteins will be assessed in a semiquantitative manner (negative, 1+, 2+, 3+) in different tumor areas. I will compare the expression of immunomodulatory proteins assessed on human prostate cancer biopsies under hormonal treatment with same-patient pre-treatment therapy biopsies.
Emergence of a senescent phenotype
时间窗: From enrollment to 24 months
The investigators will confirm in vivo, in human samples, the senescent phenotype described in prostate cancer preclinical models, assessing the SA-Beta-Gal activity on fresh OCT-embedded biopsies and/or testing the telomere shortening in FFPE biopsies, depending If will be feasible to collect both fresh frozen and FFPE cores biopsies.
Changes in expression of prostate cancer-specific markers and therapeutic targets.
时间窗: From enrollment to 24 months
The investigators will also test the expression of prostate cancer specific markers PSMA, STEAP1, STEAP2 in response to AR blockade by IHC in pre-treatment vs post-treatment samples.
次要结局
未报告次要终点
研究者
Francesca Zacchi
Medical Doctor
Universita di Verona