Glioblastoma (GBM) is the most common primary brain tumor in adults, and accounts for 20% of all primary brain tumors. GBM has a median survival rate of only 14.6 months despite current best treatment practices which include surgery and chemoradiation. A significant reason for this morbidity and mortality is the ability of GBM to invade normal brain parenchyma, making localized treatment ineffective. In order for treatment to be effective, these invading cells need to be targeted. One promising approach involves the use of mesenchymal stem cells (MSCs), which have been found by our group and by others to migrate preferentially to cancer cells. Moreover, MSCs can be engineered to synthesize and release anti-tumor proteins, such as bone morphogenic protein 4 (BMP4), which has been found to affect brain tumor initiating cells (BTICs). MSCs can be obtained from bone marrow (BM-MSC) and adipose tissue (AMSC). The use of BM-MSCs has been limited because these cells are difficult to obtain, have limited ex vivo proliferation capacity, and decrease in effectiveness with increasing donor age. AMSCs may therefore be a better option. In this grant, we propose to use a novel source for human MSCs, adipose tissue from our patients, and genetically modify these cells to secrete BMP4 for the treatment of GBM. In contrast to BM-MSCs, human AMSCs (hAMSCs) provide a therapeutically comparable source of cells which are more readily accessible and have better ex vivo expansibility. Our overall hypothesis is that virally-modified hAMSCs expressing BMP4 in combination with adjuvant radiotherapy constitute an effective treatment against intracranial GBM. To achieve these goals, we will pursue the following specific aims:
(Aim 1) To determine the tumor tropism, endothelial adherence, blood brain barrier crossing capability, and anti-glioma response of virally-modified BMP4-secreting primary hAMSCs in vitro-we have shown this with commercial hAMSCs and we propose to do it now with Freshly extracted Adipose Tissue (F.A.T.);
(Aim 2) To determine the safety and efficacy of virally-modified BMP4-secreting hAMSCs in combination with targeted radiation therapy on human GBM in an in vivo murine model. The techniques to be used in vitro and in vivo in this proposal have been developed and further characterized by our team and by our collaborators. In vitro studies will be conducted using new advancements in the fields of microfluidics and nanobiotechnology. In vivo studies will employ a mammalian xenograft model that engrafts human BTIC- derived GBM, which bests recapitulates human GBM. Additionally, we will use the small animal radiation research platform (SARRP), a novel device developed and used by our team and collaborators, which allows the delivery of targeted beams of radiation therapy to tumor-bearing mice analogous to confocal beam therapy in humans. The SARRP is capable of focusing a beam of radiation with an accuracy of 0.2 mm, recreating radiotherapy for humans on the scale of a mouse. In addition to our experiments on commercial hAMSCs, we will obtain primary hAMSCs intraoperatively from human patients and test their anti-tumor efficacy to maximize the clinical translatability of this study. The results of this stuy will demonstrate whether hAMSCs can provide a treatment that is safe and effective for not only patients with GBM, but many types of primary and metastatic brain cancers. The results of this study may likely lead to clinical trials, with a revolutionary new way of treating patients with brin cancer.

Public Health Relevance

Glioblastoma is characterized by cells with the ability to escape tumor bulk and invade normal parenchyma, making local therapies ineffective and leading to inevitable recurrence and shortened survival. We aim to use intraoperatively-obtained human adipose tissue to isolate mesenchymal stem cells, engineer these cells to secrete an anti-tumor protein, bone morphogenic protein 4, and assess their therapeutic efficiency on a murine model of brain tumor initiating cell-derived human glioblastoma in conjunction with targeted radiotherapy. These findings may lead to a new, more effective way to treat a currently incurable cancer that plagues tens of thousands of people each year, and may also translate into better treatments for other types of cancers including metastatic brain cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA183827-04
Application #
9415663
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Welch, Anthony R
Project Start
2015-05-08
Project End
2020-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
Sarabia-Estrada, Rachel; Ruiz-Valls, Alejandro; Guerrero-Cazares, Hugo et al. (2017) Metastatic human breast cancer to the spine produces mechanical hyperalgesia and gait deficits in rodents. Spine J 17:1325-1334
Mangraviti, Antonella; Tzeng, Stephany Y; Gullotti, David et al. (2016) Non-virally engineered human adipose mesenchymal stem cells produce BMP4, target brain tumors, and extend survival. Biomaterials 100:53-66
Smith, Chris L; Chaichana, Kaisorn L; Lee, Young M et al. (2015) Pre-exposure of human adipose mesenchymal stem cells to soluble factors enhances their homing to brain cancer. Stem Cells Transl Med 4:239-51
Zhu, Mingxin; Feng, Yun; Dangelmajer, Sean et al. (2015) Human cerebrospinal fluid regulates proliferation and migration of stem cells through insulin-like growth factor-1. Stem Cells Dev 24:160-71
Feng, Y; Zhu, M; Dangelmajer, S et al. (2014) Hypoxia-cultured human adipose-derived mesenchymal stem cells are non-oncogenic and have enhanced viability, motility, and tropism to brain cancer. Cell Death Dis 5:e1567