Non-BRCA DNA Damage Repair Gene Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-Resistant Prostate Cancer: analysis from the phase 2 TRITON2 study.
非 BRCA DNA 损伤修复基因改变和 PARP 抑制剂 Rucaparib 在转移性去势抵抗性前列腺癌中的反应: 来自 2 期 TRITON2 研究的分析。
- 作者列表："Abida W","Campbell D","Patnaik A","Shapiro JD","Sautois B","Vogelzang NJ","Voog EG","Bryce AH","McDermott R","Ricci F","Rowe J","Zhang J","Piulats JM","Fizazi K","Merseburger AS","Higano CS","Krieger LE","Ryan CJ","Feng FY","Simmons AD","Loehr A","Despain D","Dowson M","Green F","Watkins SP","Golsorkhi T","Chowdhury S
PURPOSE:Genomic alterations in DNA damage repair (DDR) genes other than BRCA may confer synthetic lethality with PARP inhibition in metastatic castration-resistant prostate cancer (mCRPC). To test this hypothesis, the phase 2 TRITON2 study of rucaparib included patients with mCRPC and deleterious non-BRCA DDR gene alterations. PATIENTS AND METHODS:TRITON2 enrolled patients who had progressed on 1 to 2 lines of next-generation androgen receptor (AR)-directed therapy and 1 taxane-based chemotherapy for mCRPC. Key endpoints were investigator-assessed radiographic response per modified RECIST/PCWG3 and prostate-specific antigen (PSA) response (≥50% decrease from baseline). RESULTS:TRITON2 enrolled 78 patients with a non-BRCA DDR gene alteration (ATM [n = 49], CDK12 [n = 15], CHEK2 [n = 12], and other DDR genes [n = 14]). Among patients evaluable for each endpoint, radiographic and PSA responses were observed in a limited number of patients with an alteration in ATM (2/19 [10.5%] and 2/49 [4.1%], respectively), CDK12 (0/10 [0%] and 1/15 [6.7%], respectively), or CHEK2 (1/9 [11.1%] and 2/12 [16.7%], respectively), including no radiographic or PSA responses in 11 patients with confirmed biallelic ATM loss or 11 patients with ATM germline mutations. Responses were observed in patients with alterations in the DDR genes PALB2, FANCA, BRIP1, and RAD51B. Conclusions: In this prospective, genomics-driven study of rucaparib in mCRPC, we found limited radiographic/PSA responses to PARP inhibition in men with alterations in ATM, CDK12, or CHEK2 However, patients with alterations in other DDR-associated genes (eg, PALB2) may benefit from PARP inhibition.
目的: 在转移性去势抵抗性前列腺癌 (mCRPC) 中，除 BRCA 外，DNA 损伤修复 (DDR) 基因的基因组改变可能赋予 PARP 抑制的合成致死性。为了验证这一假设，rucaparib 的 2 期 TRITON2 研究包括 mCRPC 和有害的非 BRCA DDR 基因改变的患者。 患者和方法: TRITON2 入组了接受 1 ~ 2 行新一代雄激素受体 (AR) 导向治疗和 1 例基于紫杉烷的 mCRPC 化疗的患者。关键终点是研究者根据改良 RECIST/PCWG3 评估的影像学反应和前列腺特异性抗原 (PSA) 反应 (较基线下降 ≥ 50%)。 结果: TRITON2 入选了 78 例非 BRCA DDR 基因改变的患者 (ATM [n = 49]，CDK12 [n = 15]，CHEK2 [n = 12], 和其他 DDR 基因 [n = 14])。在可评估每个终点的患者中，在 ATM 改变的有限数量患者中观察到影像学和 PSA 反应 (分别为 2/19 [10.5%] 和 2/49 [4.1%])。 CDK12 (分别为 0/10 [0%] 和 1/15 [6.7%])，或 CHEK2 (1/9 [11.1%] 和 2/12[分别为 16.7%])，包括 11 例确诊双等位基因 ATM 缺失或 11 例 ATM 种系突变患者无影像学或 PSA 反应。在 DDR 基因 PALB2 、 FANCA 、 BRIP1 和 RAD51B 改变的患者中观察到应答。结论: 在 mCRPC 中 rucaparib 的这项前瞻性、基因组学驱动的研究中，我们发现在 ATM 、 CDK12 或 CHEK2 改变的男性中，对 PARP 抑制的放射学/PSA 反应有限, 其他 DDR 相关基因 (如 PALB2) 发生改变的患者可能受益于 PARP 抑制。
METHODS::In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectability, although the risk of metastatic recurrence remains high after CLM ablation. We investigated the role of antitumour immunity invoked by first-line oxaliplatin-HAI for long-term CLM outcome. In a prospective study cohort of primarily unresectable CLM, we assessed patients' fms-related tyrosine kinase 3 ligand (FLT3LG) in serum, reflecting opportune intratumoural immune activity, at baseline and following 1-3 sequences of oxaliplatin-HAI. The end points were CLM resectability and overall survival. Patients who presented an immediate twofold increment of circulating FLT3LG during the treatment and at its completion were scored as CLM resectable (16.4% with both features), were alive at final follow-up 8-12 years later. All patients experienced FLT3LG increase during the treatment course, but those who remained unresectable or had the disease converted but presented a slow and gradual FLT3LG accretion, later died of the metastatic disease. These data provide further support to our previous findings that tumour-directed immunity invoked by oxaliplatin-containing therapy predicts excellent outcome of early advanced CRC if macroscopic tumour ablation is rendered possible by the 'classic' tumour response to the cytotoxic treatment.
METHODS::Prostate cancer is one of the primary causes of death around the world. As an important drug, flutamide has been used in the clinical diagnosis of prostate cancer. However, the over dosage and improper discharge of flutamide could affect the living organism. Thus, it necessary to develop the sensor for detection of flutamide with highly sensitivity. In this paper, we report the synthesis of lanthanum cobaltite decorated halloysite nanotube (LCO/HNT) nanocomposite prepared by a facile method and evaluated for selective reduction of flutamide. The as-prepared LCO/HNT nanocomposite shows the best catalytic performance towards detection of flutamide, when compared to other bare and modified electrodes. The good electrochemical performance of the LCO/HNT nanocomposite modified electrode is ascribed to abundant active sites, large specific surface area and their synergetic effects. Furthermore, the LCO/HNT modified electrode exhibits low detection limit (0.002 μM), wide working range (0.009-145 μM) and excellent selectivity with remarkable stability. Meaningfully, the developed electrochemical sensor was applied in real environmental samples with an acceptable recovery range.
METHODS::Several studies have indicated that cancer-associated fibroblasts (CAFs) could promote cancer progression in many malignancies. However, the mechanism by which CAFs promote the growth and metastasis of lung cancer remains poorly defined. In the present study, CAFs and normal fibroblasts (NFs) were isolated from human lung cancer and adjacent tissue. The data showed that the conditional medium (CM) of CAFs could increase the proliferation, migration and invasion of lung cancer cells. Vascular cell adhesion molecule-1 (VCAM-1) showed a higher expression in CAF-CM than NF-CM, and blocking VCAM-1 in CAF-CM attenuated the proliferation and invasion of cancer cells. Further, the results showed that VCAM-1 secreted from CAFs activated AKT and MAPK signaling via receptor α4β1 integrin (very-late antigen (VLA)-4) in lung cancer cells. Moreover, CAFs promoted VCAM-1 expression and tumor growth in vivo. Additionally, bioinformatics analysis indicated a positive correlation on the CAF marker protein alpha-smooth muscle actin (α-SMA) and VCAM-1 expression, which was associated with a poor prognosis in lung cancer patients. These findings demonstrate that the VCAM-1 secreted from CAFs enhances growth and invasion by activating the AKT and MAPK signaling of lung cancer cells.