Translational Impact of Nanoparticle–Drug Conjugate CRLX101 with or without Bevacizumab in Advanced Ovarian Cancer

Pham, Elizabeth; Birrer, Michael J.; Eliasof, Scott; Garmey, Edward G.; Lazarus, Douglas; Lee, Christina R.; Man, Shan; Matulonis, Ursula A.; Peters, Christian; Xu, Ping; Krasner, Carolyn; Kerbel, Robert S.

doi:10.1158/1078-0432.ccr-14-2810

Cited by 72 publications

(49 citation statements)

References 50 publications

(70 reference statements)

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“…CA IX expression is driven directly by HIF-1α and can be used to measure HIF-1α activity. The decreased expression of CA IX in the posttreatment tumors is consistent with the inhibitor effect of CRLX101 on HIF-1α expression, which has been previously observed (7,15). CPT has been known to cause rapid degradation of Topo-I through the ubiquitin-proteasome system in tissue culture (16)(17)(18)(19)(20).…”

Section: Discussionsupporting

confidence: 85%

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CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing

Clark

Wiley

Zuckerman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

141

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Nanoparticle-based therapeutics are being used to treat patients with solid tumors. Whereas nanoparticles have been shown to preferentially accumulate in solid tumors of animal models, there is little evidence to prove that intact nanoparticles localize to solid tumors of humans when systemically administered. Here, tumor and adjacent, nonneoplastic tissue biopsies are obtained through endoscopic capture from patients with gastric, gastroesophageal, or esophageal cancer who are administered the nanoparticle CRLX101. Both the pre-and postdosing tissue samples adjacent to tumors show no definitive evidence of either the nanoparticle or its drug payload (camptothecin, CPT) contained within the nanoparticle. Similar results are obtained from the predosing tumor samples. However, in nine of nine patients that were evaluated, CPT is detected in the tumor tissue collected 24-48 h after CRLX101 administration. For five of these patients, evidence of the intact deposition of CRLX101 nanoparticles in the tumor tissue is obtained. Indications of CPT pharmacodynamics from tumor biomarkers such as carbonic anhydrase IX and topoisomerase I by immunohistochemistry show clear evidence of biological activity from the delivered CPT in the posttreatment tumors.nanomedicine | clinical trial | gastric cancer | tumor targeting | nanoparticles N anoparticle-based experimental therapeutics are being used to deliver a variety of different drug molecules to patients with solid tumors (1). Nanoparticle delivery seeks to improve pharmacokinetic (PK) properties (e.g., enhanced solubility of the drug, increased circulation times), alter biodistribution of the drug molecules to have low amounts of drugs in nontarget tissues and increased amounts in tumors, and enhance pharmacodynamics (PD) (e.g., tunable release of the drug at the site of action in the tumor) to produce enhanced efficacy while simultaneously reducing side effects (and most importantly, introducing no new side effects due to the nanoparticle) in patients. These properties can: (i) enable drug combinations formerly prohibited by toxicity limits, (ii) enable new classes of drug delivery [for example, short interfering RNAs (siRNAs)], and (iii) provide cell-specific targeting within a tumor.Delivery of drugs to solid tumors using nanoparticle technology relies on the enhanced permeability and retention (EPR) effect. The mechanistic data regarding the EPR effect come from animal models, primarily xenografted human tumors in mice. Because these xenografted tumors poorly recapitulate the architecture of true human tumors, there is skepticism about whether or not intact nanoparticles can localize in human tumors. Radiolabeled liposomes have been used to assess tumor accumulation in humans (2, 3). In those studies, the amounts of radioactivity accumulated in tumors did correlate with the number of microvessels measured from nine patient biopsies (3). Increased microvessel density may be an indication of increasing potential for the EPR effect. Also, Davis et al. demonstrated dose-depe...

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Section: Discussionsupporting

confidence: 85%

“…1A). CRLX101 is currently in a number of human cancer phase II trials (early results from some of the phase I/II trials are available) (6,7). Here, a clinical trial was performed at and sponsored by the City of Hope Comprehensive Cancer Center (ClinicalTrials.gov identifier: NCT01612546).…”

mentioning

confidence: 99%

CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing

Clark

Wiley

Zuckerman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

141

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“…CRLX101 was designed to have improved accumulation within tumors by the enhanced permeability and retention (EPR) effect and thus reduced systemic exposure and toxicity (8,20). The drug has been administered to more than 300 patients to date and appears to be generally well tolerated, achieving an overall response rate of 16% in 19 patients in a phase II clinical trial of platinum-resistant ovarian cancer as a monotherapy (23) and 23% in 22 patients in a phase I/II study of metastatic renal cell carcinoma in combination with bevacizumab (21).…”

Section: Introductionmentioning

confidence: 99%

“…We recently reported that CRLX101 plus bevacizumab resulted in synergistic antitumor efficacy in a preclinical model of advanced, metastatic ovarian cancer (23). CRLX101 was also shown to effectively and durably suppress elevated hypoxiainduced upregulation of hypoxia-inducible factor-1a (HIF1a) following therapy with bevacizumab, thus downregulating expression of downstream HIF1a-regulated markers, such as carbonic anhydrase IX (CAIX; ref.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Efficacy of Bevacizumab with CRLX101, an Investigational Nanoparticle–Drug Conjugate, in Treatment of Metastatic Triple-Negative Breast Cancer

et al. 2016

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VEGF pathway-targeting antiangiogenic drugs, such as bevacizumab, when combined with chemotherapy have changed clinical practice for the treatment of a broad spectrum of human cancers. However, adaptive resistance often develops, and one major mechanism is elevated tumor hypoxia and upregulated hypoxia-inducible factor-1a (HIF1a) caused by antiangiogenic treatment. Reduced tumor vessel numbers and function following antiangiogenic therapy may also affect intratumoral delivery of concurrently administered chemotherapy. Nonetheless, combining chemotherapy and bevacizumab can lead to improved response rates, progression-free survival, and sometimes, overall survival, the extent of which can partly depend on the chemotherapy backbone. A rational, complementing chemotherapy partner for combination with bevacizumab would not only reduce HIF1a to overcome hypoxia-induced resistance, but also improve tumor perfusion to maintain intratumoral drug delivery. Here, we evaluated bevacizumab and CRLX101, an investigational nanoparticle-drug conjugate containing camptothecin, in preclinical mouse models of orthotopic primary triple-negative breast tumor xenografts, including a patient-derived xenograft. We also evaluated long-term efficacy of CRLX101 and bevacizumab to treat postsurgical, advanced metastatic breast cancer in mice. CRLX101 alone and combined with bevacizumab was highly efficacious, leading to complete tumor regressions, reduced metastasis, and greatly extended survival of mice with metastatic disease. Moreover, CRLX101 led to improved tumor perfusion and reduced hypoxia, as measured by contrast-enhanced ultrasound and photoacoustic imaging. CRLX101 durably suppressed HIF1a, thus potentially counteracting undesirable effects of elevated tumor hypoxia caused by bevacizumab. Our preclinical results show pairing a potent cytotoxic nanoparticle chemotherapeutic that complements and improves concurrent antiangiogenic therapy may be a promising treatment strategy for metastatic breast cancer. Cancer Res; 76(15); 4493-503. Ó2016 AACR.

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“…There are multiple reasons for this, one cause may be that ovarian carcinoma is generally detected late, almost 70% of all patients present with advanced stage III and IV cancer, and a number of patients are misdiagnosed (3)(4)(5). The majority of patients suffer from abdominal, gastrointestinal, urinary, or pelvic pain, which rarely lead to timely definitive diagnosis, leading to the generally late detection of ovarian carcinomas (6,7).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of SASH1 correlates with tumor progression and poor prognosis in ovarian carcinoma

et al. 2016

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Abstract. SAM-and SH3-domain containing 1 (SASH1) is a recently identified tumor suppressor gene that is required in the tumorigenesis of breast and other solid carcinomas. The SASH1 protein contains SH3 and SAM domains, indicating that it may serve an important role in intracellular signal transduction. The purpose of the present study was to investigate the expression of SASH1 in ovarian carcinoma and the correlation between its expression with clinical pathological features and clinical significance, and the effect of SASH1 on cell proliferation, apoptosis and migration of ovarian SKOV3 cells. The human ovarian carcinoma tissues and adjacent normal tissues were collected following surgery. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to detect the expression levels of SASH1 mRNA and protein, respectively. The expression levels of SASH1 mRNA and protein in ovarian carcinoma tissues were significantly lower than that observed in adjacent normal tissues (P<0.05). The expression levels of SASH1 in samples from patients without lymph nodes metastasis and patients with early FIGO stage was lower than those with lymph nodes metastasis and patients with advanced FIGO stage (P<0.05). Flow cytometry analysis and Transwell invasion chamber experiments were used to investigate the effect of SASH1 on the cell proliferation, apoptosis and migration of SKOV3 cells. The recombinant plasmid pcDNA3.1-SASH1 was constructed and transfected into SKOV3 cells. In addition, the SKOV3 cells in the pcDNA3.1-SASH1 group exhibited significantly reduced cell growth, proliferation, and migration ability compared to the empty vector group and normal group (P<0.01). There were a greater number of apoptotic cells in the pcDNA3.1-SASH1 group compared to the empty vector group and normal group (P<0.01). Taken together, these results indicated that SASH1 may be a tumor suppressor gene in ovarian carcinoma, and SASH1 expression inhibited growth, proliferation and migration, and enhanced apoptosis of SKOV3 cells.

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Translational Impact of Nanoparticle–Drug Conjugate CRLX101 with or without Bevacizumab in Advanced Ovarian Cancer

Cited by 72 publications

References 50 publications

CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing

CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing

Preclinical Efficacy of Bevacizumab with CRLX101, an Investigational Nanoparticle–Drug Conjugate, in Treatment of Metastatic Triple-Negative Breast Cancer

Downregulation of SASH1 correlates with tumor progression and poor prognosis in ovarian carcinoma

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