Heparanase in Tumor Progression, Metastasis and Chemoresistance
Heparanase in Tumor Progression, Metastasis and Chemoresistance
批准号:
10171563
负责人:
Ralph D Sanderson
金额:
$34.2万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-06-15 至 2023-05-31
关键词:
Aggressive behaviorAnimal ModelAutomobile DrivingBiological ModelsCancer ModelCancer PatientCancer cell lineCellsChemicalsChemoresistanceClinicClinical TrialsCouplesDevelopmentDockingExhibitsExposure toGoalsGrowthHeparanase inhibitorsHeparinIn VitroInvestigationKnockout MiceKnowledgeMalignant NeoplasmsMediatingMediator of activation proteinMonoclonal AntibodiesMultiple MyelomaMusNeoplasm MetastasisOutcomePancreatic carcinomaPathway interactionsPatient-Focused OutcomesPatientsPharmaceutical PreparationsPhase I Clinical TrialsPhenotypePlayPre-Clinical ModelPrimary NeoplasmProbabilityProteinsRegulationResistanceResourcesRoleSpecificityStromal CellsTestingTherapeuticTransgenic MiceTumor BiologyTumor-DerivedWorkanti-cancer therapeuticantitumor effectcancer cellcancer therapychemotherapydesignexosomeexperienceheparanaseimprovedin vivoinnovationmacrophageneoplastic cellnovelpancreatic cancer cellspre-clinicalsuccesstargeted cancer therapytargeted treatmenttooltumortumor behaviortumor growthtumor initiationtumor microenvironmenttumor progression
中文摘要
我们工作的长期目标是了解肝素酶如何促进
英文摘要
The long-term goal of our work is to understand how heparanase promotes the
aggressive behavior of tumors and to use that knowledge to develop curative cancer therapies. We have
identified multiple mechanisms through which heparanase drives cancer progression, metastasis and
chemoresistance and established heparanase as a viable target for cancer therapy. Moreover, we catalyzed
collaborative efforts aimed at developing and testing novel anti-heparanase drugs and demonstrated their
efficacy in pre-clinical models of cancer leading to a currently ongoing clinical trial. The challenge now is to
maximize anti-heparanase therapy to enhance its anti-tumor effects; a goal that will be attained through a
thorough understanding of heparanase mechanisms of action. The overarching hypothesis guiding our work is
that heparanase is a master regulator of the aggressive phenotype of cancer, an important contributor
to the poor outcome of many cancer patients and a prime target for therapy. This hypothesis is supported
by studies focused predominantly on the impact of heparanase expressed by tumor cells. Our latest
discoveries have revealed two novel, previously unexplored mechanisms related to heparanase regulation of
cancer. We found that: (i) heparanase expressed by non-tumor (host) cells within the microenvironment can
substantially contribute to tumor progression, and (ii) tumor secreted exosomes can shuttle heparanase to
recipient cells and enhance their chemoresistance. Our working hypothesis for Aim 1 is that heparanase
produced by host cells acts within the tumor microenvironment to support and accelerate tumor growth,
metastasis and chemoresistance. This will be studied in pancreatic carcinoma and myeloma tumors growing in
mice that express different levels of host heparanase (transgenic and knockout mice). We will investigate the
type of host cells involved (e.g., macrophages, stromal cells), their impact on tumor progression and
chemoresistance and the ability of heparanase inhibitors to block those effects of host heparanase. Our
working hypothesis for Aim 2 is that heparanase present as cargo in exosomes is delivered to recipient tumor
cells and enhances their chemoresistance. We will determine mechanistically how exosomes drive
chemoresistance and investigate the potential of anti-heparanase therapy for inhibiting exosome-mediated
chemoresistance. In addition, work in Aim 3 will develop new, highly specific anti-heparanase monoclonal
antibodies as anti-cancer therapeutics. The proposed work is significant and innovative because it couples the
discovery of new heparanase mechanisms of action with the objective of maximizing anti-heparanase therapy
and improving patient outcome.
期刊论文(13)
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DOI:
10.1016/j.canlet.2020.08.022
发表时间:
2020-11-28
期刊:
Cancer letters
影响因子:
9.7
作者:
[Bandari SK, Tripathi K, Rangarajan S, Sanderson RD]
通讯作者:
Sanderson RD
DOI:
10.1016/j.matbio.2017.10.007
发表时间:
2019-01
期刊:
Matrix biology : journal of the International Society for Matrix Biology
影响因子:
--
作者:
[Sanderson RD, Bandari SK, Vlodavsky I]
通讯作者:
Vlodavsky I
DOI:
10.3390/cells9092038
发表时间:
2020-09-06
期刊:
Cells
影响因子:
6
作者:
[Amin R, Tripathi K, Sanderson RD]
通讯作者:
Sanderson RD
DOI:
10.1016/j.tibs.2017.10.007
发表时间:
2018-01
期刊:
Trends in biochemical sciences
影响因子:
13.8
作者:
[Vlodavsky I, Gross-Cohen M, Weissmann M, Ilan N, Sanderson RD]
通讯作者:
Sanderson RD
DOI:
10.1007/978-3-030-34521-1_12
发表时间:
2020
期刊:
Advances in experimental medicine and biology
影响因子:
--
作者:
[Purushothaman A, Sanderson RD]
通讯作者:
Sanderson RD
共 6 条
Novel Heparanase Inhibitors for Cancer Therapy
-
批准号:8018508
-
项目类别:
-
资助金额:$33.39万
-
财政年份:2010
-
负责人:Ralph D Sanderson
-
依托单位:
Novel Heparanase Inhibitors for Cancer Therapy
-
批准号:8600889
-
项目类别:
-
资助金额:$35.24万
-
财政年份:2010
-
负责人:Ralph D Sanderson
-
依托单位:
Novel Heparanase Inhibitors for Cancer Therapy
-
批准号:8403830
-
项目类别:
-
资助金额:$37.27万
-
财政年份:2010
-
负责人:Ralph D Sanderson
-
依托单位:
Novel Heparanase Inhibitors for Cancer Therapy
-
批准号:7779594
-
项目类别:
-
资助金额:$36.85万
-
财政年份:2010
-
负责人:Ralph D Sanderson
-
依托单位:
Novel Heparanase Inhibitors for Cancer Therapy
-
批准号:8204594
-
项目类别:
-
资助金额:$40.33万
-
财政年份:2010
-
负责人:Ralph D Sanderson
-
依托单位:
Heparanase Regulation of Myeloma Metastasis: Mechanism and Therapy
-
批准号:7623792
-
项目类别:
-
资助金额:$36.78万
-
财政年份:2009
-
负责人:Ralph D Sanderson
-
依托单位:
Heparanase Regulation of Myeloma Metastasis: Mechanism and Therapy
-
批准号:8259527
-
项目类别:
-
资助金额:$33.02万
-
财政年份:2009
-
负责人:Ralph D Sanderson
-
依托单位:
Heparanase Regulation of Myeloma Metastasis: Mechanism and Therapy
-
批准号:8464021
-
项目类别:
-
资助金额:$30.83万
-
财政年份:2009
-
负责人:Ralph D Sanderson
-
依托单位:
Heparanase Regulation of Myeloma Metastasis: Mechanism and Therapy
-
批准号:8065432
-
项目类别:
-
资助金额:$33.1万
-
财政年份:2009
-
负责人:Ralph D Sanderson
-
依托单位:
Heparanase regulation of tumor host interactions in myeloma and breast cancer
-
批准号:8300186
-
项目类别:
-
资助金额:$29.12万
-
财政年份:2008
-
负责人:Ralph D Sanderson
-
依托单位:
Heparanase regulation of tumor host interactions in myeloma and breast cancer
-
批准号:8115999
-
项目类别:
-
资助金额:$29.12万
-
财政年份:2008
-
负责人:Ralph D Sanderson
-
依托单位:
Heparanase regulation of tumor host interactions in myeloma and breast cancer
-
批准号:7682576
-
项目类别:
-
资助金额:$29.43万
-
财政年份:2008
-
负责人:Ralph D Sanderson
-
依托单位:
Targeting Heparan Sulfate for Myeloma Therapy
-
批准号:6997915
-
项目类别:
-
资助金额:$18.83万
-
财政年份:2004
-
负责人:Ralph D Sanderson
-
依托单位:
Role of heparanase in osteolytic bone metastasis
-
批准号:7281610
-
项目类别:
-
资助金额:$30.42万
-
财政年份:2003
-
负责人:Ralph D Sanderson
-
依托单位:
Role of heparanase in osteolytic bone metastasis
-
批准号:7275041
-
项目类别:
-
资助金额:$4.26万
-
财政年份:2003
-
负责人:Ralph D Sanderson
-
依托单位:
Role of heparanase in osteolytic bone metastasis
-
批准号:7111101
-
项目类别:
-
资助金额:$31.35万
-
财政年份:2003
-
负责人:Ralph D Sanderson
-
依托单位:
Role of heparanase in osteolytic bone metastasis
-
批准号:7233092
-
项目类别:
-
资助金额:$26.0万
-
财政年份:2003
-
负责人:Ralph D Sanderson
-
依托单位:
Role of heparanase in osteolytic bone metastasis
-
批准号:7117890
-
项目类别:
-
资助金额:$1.77万
-
财政年份:2003
-
负责人:Ralph D Sanderson
-
依托单位:
Role of heparanase in osteolytic bone metastasis
-
批准号:6940634
-
项目类别:
-
资助金额:$8.62万
-
财政年份:2003
-
负责人:Ralph D Sanderson
-
依托单位:
Role of heparanase in osteolytic bone metastasis
-
批准号:6795480
-
项目类别:
-
资助金额:$31.43万
-
财政年份:2003
-
负责人:Ralph D Sanderson
-
依托单位:
海外基金