Antimetastatic Properties of Low Molecular Weight Heparin

Läubli, Heinz; Varki, Ajit; Borsig, Lubor

doi:10.1200/jco.2016.66.4607

Cited by 9 publications

(6 citation statements)

References 6 publications

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“…Phase I studies of PQR309 in patients with advanced solid tumors show that and the most frequent adverse events are fatigue, hyperglycemia, nausea, diarrhea, constipation, rash, anorexia and vomiting. Concentration-dependent hyperglycemia has been confirmed as a mechanism-based toxicity of PQR309 (NCT01940133, NCT02483858) [107, 108]. A non-randomized phase II study in patients with progressive GBM is ongoing to evaluate the safety, efficacy, pharmacokinetics and pharmacodynamic effects of PQR309 (NCT02850744).…”

Section: Introductionmentioning

confidence: 99%

Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development

et al. 2017

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Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary tumor in the central nervous system. One of the most widely used chemotherapeutic drugs for GBM is temozolomide, which is a DNA-alkylating agent and its efficacy is dependent on MGMT methylation status. Little progress in improving the prognosis of GBM patients has been made in the past ten years, urging the development of more effective molecular targeted therapies. Hyper-activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is frequently found in a variety of cancers including GBM, and it plays a central role in the regulation of tumor cell survival, growth, motility, angiogenesis and metabolism. Numerous PI3K inhibitors including pan-PI3K, isoform-selective and dual PI3K/mammalian target of rapamycin (mTOR) inhibitors have exhibited favorable preclinical results and entered clinical trials in a range of hematologic malignancies and solid tumors. Furthermore, combination of inhibitors targeting PI3K and other related pathways may exert synergism on suppressing tumor growth and improving patients’ prognosis. Currently, only a handful of PI3K inhibitors are in phase I/II clinical trials for GBM treatment. In this review, we focus on the importance of PI3K/Akt pathway in GBM, and summarize the current development of PI3K inhibitors alone or in combination with other inhibitors for GBM treatment from preclinical to clinical studies.

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Section: Introductionmentioning

confidence: 99%

Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development

et al. 2017

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“…The widespread use of heparin as a treatment is hindered by unwanted anticoagulant side-effects [ 30 ] (see also review by Afratis et al [ 31 ]); however, the possibility of correcting signaling defects caused by altered HS structure (e.g., by sulf enzyme activity) in cancer [ 32 , 33 ] or the direct inhibition of the sulf enzymes with heparin or heparin analogues is an area of potential interest. Of direct relevance to the progression of the disease is the inhibition of a mammalian heparanase enzyme [ 34 ], while other routes are thought to influence metastasis, acting via P- and L-selections [ 35 , 36 , 37 ], inhibiting galectins [ 38 ], inhibiting tumorogenesis and angiogenesis through cellular receptors such as CD44 and growth factor receptors [ 39 ], or, in the case of the use of heparin as a means of ameliorating resistance to cisplatin treatment, acting through as-yet unidentified mechanisms [ 40 ], all of which are affected by heparin or heparin analogues. Among other GAGs, an example of the treatment of cancer is the use of the non-sulfated GAG, hyaluronate (HA) in pancreatic ductal adenocarcinoma [ 41 ].…”

Section: Applications In Anticoagulation and Cancer Treatmentsmentioning

confidence: 99%

New Applications of Heparin and Other Glycosaminoglycans

2017

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Heparin, the widely used pharmaceutical anticoagulant, has been in clinical use for well over half a century. Its introduction reduced clotting risks substantially and subsequent developments, including the introduction of low-molecular-weight heparin, made possible many major surgical interventions that today make heparin an indispensable drug. There has been a recent burgeoning of interest in heparin and related glycosaminoglycan (GAG) polysaccharides, such as chondroitin sulfates, heparan sulfate, and hyaluronate, as potential agents in various applications. This ability arises mainly from the ability of GAGs to interact with, and alter the activity of, a wide range of proteins. Here, we review new developments (since 2010) in the application of heparin and related GAGs across diverse fields ranging from thrombosis and neurodegenerative disorders to microbiology and biotechnology.

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“…The perioperative period might be the ideal setting to study the antimetastatic effects of low molecular weight heparin. 6 Surgery results in a hypercoagulable postoperative state and an inability to clear micrometastatic disease when the disease is present after surgical resection, leading to potential cancer recurrence and worse survival. 7 In preclinical studies, perioperative administration of low molecular weight attenuated postoperative metastatic disease by preventing platelet and fibrin binding and thereby facilitating immune-mediated destruction of tumour cell microemboli by natural killer cells.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of extended duration to perioperative thromboprophylaxis with low molecular weight heparin on disease-free survival after surgical resection of colorectal cancer (PERIOP-01): multicentre, open label, randomised controlled trial

Auer

Ott

Karanicolas

et al. 2022

BMJ

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Objective To determine the efficacy and safety of extended duration perioperative thromboprophylaxis by low molecular weight heparin when assessing disease-free survival in patients undergoing resection for colorectal cancer. Design Multicentre, open label, randomised controlled trial. Settings 12 hospitals in Quebec and Ontario, Canada, between 25 October 2011 and 31 December 2020. Participants 614 adults (age ≥18 years) were eligible with pathologically confirmed invasive adenocarcinoma of the colon or rectum, no evidence of metastatic disease, a haemoglobin concentration of ≥8 g/dL, and were scheduled to undergo surgical resection. Interventions Random assignment to extended duration thromboprophylaxis using daily subcutaneous tinzaparin at 4500 IU, beginning at decision to operate and continuing for 56 days postoperatively, compared with in-patient postoperative thromboprophylaxis only. Main outcome measures Primary outcome was disease-free survival at three years, defined as survival without locoregional recurrence, distant metastases, second primary (same cancer), second primary (other cancer), or death. Secondary outcomes included venous thromboembolism, postoperative major bleeding complications, and five year overall survival. Analyses were done in the intention-to-treat population. Results The trial stopped recruitment prematurely after the interim analysis for futility. The primary outcome occurred in 235 (77%) of 307 patients in the extended duration group and in 243 (79%) of 307 patients in the in-hospital thromboprophylaxis group (hazard ratio 1.1, 95% confidence interval 0.90 to 1.33; P=0.4). Postoperative venous thromboembolism occurred in five patients (2%) in the extended duration group and in four patients (1%) in the in-hospital thromboprophylaxis group (P=0.8). Major surgery related bleeding in the first postoperative week was reported in one person (<1%) in the extended duration and in six people (2%) in the in-hospital thromboprophylaxis group (P=0.1). No difference was noted for overall survival at five years in 272 (89%) patients in the extended duration group and 280 (91%) patients in the in-hospital thromboprophylaxis group (hazard ratio 1.12; 95% confidence interval 0.72 to 1.76; P=0.1). Conclusions Extended duration to perioperative anticoagulation with tinzaparin did not improve disease-free survival or overall survival in patients with colorectal cancer undergoing surgical resection compared with in-patient postoperative thromboprophylaxis alone. The incidences of venous thromboembolism and postoperative major bleeding were low and similar between groups. Trial registration ClinicalTrials.gov NCT01455831 .

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Antimetastatic Properties of Low Molecular Weight Heparin

Cited by 9 publications

References 6 publications

Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development

Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development

New Applications of Heparin and Other Glycosaminoglycans

Efficacy and safety of extended duration to perioperative thromboprophylaxis with low molecular weight heparin on disease-free survival after surgical resection of colorectal cancer (PERIOP-01): multicentre, open label, randomised controlled trial

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