SPARC Expression Did Not Predict Efficacy of <i>nab</i>-Paclitaxel plus Gemcitabine or Gemcitabine Alone for Metastatic Pancreatic Cancer in an Exploratory Analysis of the Phase III MPACT Trial

Hidalgo, Manuel; Plaza, Carlos; Musteanu, Mónica; Illei, Peter B.; Brachmann, Carrie Baker; Heise, Carla; Pierce, Daniel W.; López-Casas, Pedro P.; Menéndez, Camino; Tabernero, Josep; Romano, Andrea; Wei, Xinyu; López‐Ríos, Fernando; Hoff, Daniel D. Von

doi:10.1158/1078-0432.ccr-14-3222

Cited by 118 publications

(84 citation statements)

References 29 publications

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“…SPARC (secreted protein acidic and rich in cysteine) was reported to be a potential predictive biomarker of nab-paclitaxel efficacy in metastatic PC, but subsequent attempts to validate this biomarker failed in a larger scale study. (6) Given the poor outcomes associated with PC, NSCLC, and certain subtypes of breast cancer, novel therapies and biomarkers that predict efficacy are urgently needed.…”

Section: Introductionmentioning

confidence: 99%

Caveolae-Mediated Endocytosis Is Critical for Albumin Cellular Uptake and Response to Albumin-Bound Chemotherapy

et al. 2017

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Nab-paclitaxel, a nanoparticle conjugate of paclitaxel to human albumin, exhibits efficacy in pancreatic cancer, non-small cell lung cancer and breast cancer. However, there is a lack of predictive biomarkers to identify patients who might benefit most from its administration. This study addresses this gap in knowledge by identifying that caveolin-1 (Cav-1) is a candidate mechanism-based biomarker. Caveolae are small membrane invaginations important for trans-endothelial albumin uptake. Cav-1, the principal structural component of caveolae, is overexpressed in the cancers noted above which respond to nab-paclitaxel. Thus, we hypothesized that Cav-1 may be critical for albumin uptake in tumors and perhaps determine their response to this drug. Cav-1 protein levels correlated positively with nab-paclitaxel sensitivity. RNAi-mediated attenuation of Cav-1 expression reduced uptake of albumin and nab-paclitaxel in cancer cells and rendered them resistant to nab-paclitaxel-induced apoptosis. Conversely, Cav-1 overexpression enhanced sensitivity to nab-paclitaxel. Selection for cellular resistance to nab-paclitaxel in cell culture correlated with a loss of Cav-1 expression. In mouse xenograft models, cancer cells where Cav-1 was attenuated exhibited resistance to the antitumor effects of nab-paclitaxel therapy. Overall, our findings suggest Cav-1 as a predictive biomarker for the response to nab-paclitaxel and other albumin-based cancer therapeutic drugs.

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Section: Introductionmentioning

confidence: 99%

Caveolae-Mediated Endocytosis Is Critical for Albumin Cellular Uptake and Response to Albumin-Bound Chemotherapy

et al. 2017

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“…The high levels of tumoral SPARC was proposed as one mechanism for the efficacy of nanoparticulate albumin bound paclitaxel (nab-paclitaxel), owing to the capacity of SPARC to bind albumin, and in a Phase III trial of nab-paclitaxel in metastatic pancreatic, SPARC had positive association with efficacy (238, 239). However, in a mouse pancreatic cancer model, this binding effect was found to be saturable at low doses and not responsible for efficacy of the nab-paclitaxel (240).…”

Section: Introductionmentioning

confidence: 99%

Matricellular proteins in drug delivery: Therapeutic targets, active agents, and therapeutic localization

Sawyer

Kyriakides

2016

Advanced Drug Delivery Reviews

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Extracellular matrix is composed by a complex array of molecules that together provide structural and functional support to cells. These properties are mainly mediated by the activity of collagenous and elastic fibers, proteoglycans, and proteins such as fibronectin and laminin. ECM composition is tissue-specific and could include matricellular proteins whose primary role is to modulate cell-matrix interactions. In adults, matricellular proteins are primarily expressed during injury, inflammation and disease. Particularly, they are closely associated with the progression and prognosis of cardiovascular and fibrotic diseases, and cancer. This review aims to provide an overview of the potential use of matricellular proteins in drug delivery including the generation of therapeutic agents based on the properties and structures of these proteins as well as their utility as biomarkers for specific diseases.

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“…Since the study was completed, the validity of expression of the ERCC protein by the previously used batches of 8F1 antibody could not be replicated in non-small cell lung cancer and has been replaced by newer methodology (26). The usefulness of SPARC is also in question as a subset analysis of mPC patients treated with nab-paclitaxel and gemcitabine in the randomized MPACT trial did not show a benefit of treatment for SPARC overexpression (27). Additional MP was performed, with aCGH in 24 treated patients.…”

Section: Discussionmentioning

confidence: 99%

A phase 2 trial of personalized cytotoxic therapy based on tumor immunohistochemistry in previously treated metastatic pancreatic cancer patients

Ramanathan

Weiss

Posner

et al. 2017

J. Gastrointest. Oncol.

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Background: The choice of a regimen in metastatic pancreatic cancer patients following progression on 1st line therapy is empiric and outcomes are unsatisfactory. This phase II study was performed to evaluate the efficacy of therapy selected by immunohistochemistry (IHC) in these patients following progression after one or more therapies.Methods: Eligible patients underwent a percutaneous biopsy of a metastatic lesion and treatment selection was determined by IHC. The study required 35 evaluable patients (power of 86%) for detecting a true 1-year survival rate of >20%.Results: A tumor biopsy was performed in 48 of 49 accrued patients. Study therapy was not given (n=13) either due to insufficient tumor on biopsy (n=8) or due to worsening cancer related symptoms after biopsy (n=5).The demographics of evaluable patients (n=35) are male/female (59%/41%), with age range 34-78 years (median 63 years). Patients had 1-6 prior regimens (median of 2). The most common IHC targets were topoisomerase 1 or 2, thymidylate synthase, excision repair cross-complementation group 1 protein (ERCC1), and osteonectin secreted protein acidic and rich in cysteine (SPARC). Commercially available treatment regimens prescribed included FOLFIRI, FOLFOX, irinotecan, and doxorubicin. The response (RECIST) was 9%, the median survival was 5.6 months (94% CI, 3.8-8.2), and the 1-year survival was 20% (95% CI, 7-33%).Conclusions: In all patients, IHC assays resulted in identification of at least two targets for therapy and a non-cross resistant regimen could be prescribed for therapy with evidence of some benefit. An IHC based treatment strategy is feasible and needs validation in larger studies.

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SPARC Expression Did Not Predict Efficacy of nab-Paclitaxel plus Gemcitabine or Gemcitabine Alone for Metastatic Pancreatic Cancer in an Exploratory Analysis of the Phase III MPACT Trial

Cited by 118 publications

References 29 publications

Caveolae-Mediated Endocytosis Is Critical for Albumin Cellular Uptake and Response to Albumin-Bound Chemotherapy

Caveolae-Mediated Endocytosis Is Critical for Albumin Cellular Uptake and Response to Albumin-Bound Chemotherapy

Matricellular proteins in drug delivery: Therapeutic targets, active agents, and therapeutic localization

A phase 2 trial of personalized cytotoxic therapy based on tumor immunohistochemistry in previously treated metastatic pancreatic cancer patients

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