Small extracellular vesicles as biomarkers of prognosis and response to therapy in head and neck cancer

Active Project Grant Awarded Last action

Award ID
R01DE031299
Recipient
Awarding agency
Obligated
$7,794,342

Award facts

Assistance listing
93.121 Oral Diseases and Disorders Research
Completion date 76% complete
Place of performance
Pennsylvania, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Biomarkers that reliably inform the selection of therapy or prognosis for patients with head and neck squamous cell carcinoma (HNSCC) are lacking. This can result in the use of overly aggressive or ineffective therapy with the associated negative impact on quality of life and mortality. Thus, there is a great need for the development of non-invasive biomarkers that accurately predict response to therapy or prognosis of HNSCC. Emerging data suggest that analysis of the cargos of small (30-150 NM) extracellular vesicles (SEV), also known as exosomes, in body fluids is a promising approach to the detection of non-invasive biomarkers in cancer, including HNSCC. In cancer patients, plasma SEV are mixtures of tumor-derived exosomes (TEX) and vesicles produced by non- malignant cells (NTEX) such as leukocytes. We found that TEX are a prominent but variable subset of SEV in HNSCC patients' plasma. TEX recapitulate the content of tumor cells, while the molecular cargo of NTEX resembles that of non-malignant leukocytes, largely T cells, reprogrammed by TEX. Our data indicate that both these SEV subsets mediate immune suppression and influence responses to therapy. We hypothesize that in HNSCC patients, TEX as well as NTEX mediate immune suppression and are responsible for poor prognosis and resistance to anti-cancer therapies. Using a novel immune capture-based technology, we will separate TEX from NTEX in HNSCC patients' plasma and will then simultaneously evaluate these two SEV subsets as potential biomarkers. In aim 1, we will establish efficacy of the immune capture strategy for TEX and NTEX isolation from HNSCC patients' plasma and determine the potential of these SEV subsets to serve as biomarkers of cancer and immune competence, respectively. Levels as well as phenotypic profiles and immunosuppressive functions of the two SEV subsets will be evaluated and assessed for their ability to discriminate HNSCC patients from healthy donors (HDS). In addition, high-resolution (HR) LC-MS/MS will be used to identify proteins in TEX and NTEX that could be utilized as prognostic or predictive biomarkers. In aim 2, we will evaluate the utility of TEX and NTEX as biomarkers of prognosis in patients with locally advanced HNSCC treated with standard of care therapy (N=200). Utilizing TEX and NTEX isolated from well-annotated existing pre-treatment plasma samples, nanoflow cytometry, functional assays, and targeted HR LC-MS/MS will be used to assess phenotypic profiles and immunosuppressive functions. We will correlate TEX and NTEX plasma levels and profiles with clinical endpoints. In aim 3, we will investigate the utility of TEX and NTEX as biomarkers of response to anti-PD-1 MAB immunotherapy in HNSCC patients diagnosed with recurrent/metastatic disease (N=80). TEX and NTEX characteristics will be assessed as in aim 2, and we will evaluate whether they are predictive of the efficacy of anti-PD-1 MAB therapy. The simultaneous assessment of TEX and NTEX in plasma of HNSCC patients will confirm the role of these two SEV subsets as biomarkers of cancer as well as of cancer-induced defects in immune competence. Importantly, these biomarkers, alone or together, have the potential to guide selections of therapies that will improve outcome and reduce morbidity and mortality in patients with HNSCC.

Transactions

Action Obligated Date
Amendment $70,004
Amendment $630,033
Amendment $630,033
Amendment $70,004
Amendment $630,033
Amendment $0
Amendment $0
Amendment $630,033
Amendment $56,003
Amendment $56,003
Amendment $56,003
Amendment $130,976
Amendment $130,976
Amendment $130,976
Amendment $130,976
Amendment $630,033
Amendment $630,033
Amendment $630,033
Amendment $630,033
Amendment $640,719
Amendment $640,719
Original award $640,719
Show all 22

Subawards

Subrecipient Amount Awarded
The General Hospital Corporation Small extracellular vesicles as biomarkers of prognosis and response to therapy in head and neck cancer $127,068
The General Hospital Corporation $82,049
Narodowy Instytut Onkologii IM. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy $52,804
The General Hospital Corporation $82,049
Narodowy Instytut Onkologii IM. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy $36,226

Quick answers

Who received award R01DE031299?

R01DE031299 was awarded to University Of Pittsburgh - Of The Commonwealth System Of Higher Education by National Institute of Dental and Craniofacial Research (National Institutes of Health) on March 15, 2023.

How much is award R01DE031299 worth?

$7,794,342 has been obligated on R01DE031299.

On GovTribe

See this award's full record

  • Every transaction and subaward
  • The recipient's other awards and teaming partners
  • Similar grant awards
  • Ask GovTribe AI about this award
Try for free Login