Research Highlight


Multi-parametric PET/MR imaging in glioblastoma: FDG-PET and morphological MR image after administration of MR contrast agent (middle column). Parameters derived from the MR data (Ktrans, cerebral blood volume (CBV) and ADC) and the PET data (metabolic rate of glucose (CMRglu), K1, k3) in the region of interest (red contour) defined on the enhancing part of the tumor are shown in the left and right column, respectively. Images courtesy of Dan Chonde and Dominique Jennings.

Pharmacokinetic analysis of changes in temozolomide distribution after antiangiogenic treatment of glioblastoma

Glioblastoma (GBM) is a uniformly fatal tumor afflicting approximately 13,000 persons each year in the United States. Despite aggressive therapy with surgery, radiation and cytotoxic chemotherapy, average survival is less than 1 year and less than 4% of patients survive 5 years or more. Standard initial therapy for this tumor is maximal resection, combined daily temozolomide (TMZ) and radiation (chemoradiation) followed by monthly cycles of post-radiation temozolomide. Although the prognosis for newly diagnosed GBM patients has improved slightly with the advent of chemoradiation, the outlook is still grim in this patient population. Pathologic features of GBM include marked angiogenesis with microvascular proliferation and severe hypoxia with tumor necrosis. There is now some evidence to suggest that the anti-angiogenic agents are effective in GBM. However, the mechanisms by which these therapies exert an anti-tumor effect are not well understood. One hypothesis is that they change the delivery of chemotherapeutic agents such as TMZ. TMZ is a DNA alkylating agent used because of its excellent oral bioavailability. A spontaneous hydrolysis reaction causes the TMZ molecule to open up its heterocyclic ring at C4, producing carbon dioxide and MTIC, an unstable compound that degrades quickly into a reactive methylating compound, methyldiazonium ion. This compound can preferentially methylate a particular sequence on DNA, which causes a mismatch. Unless the methylation is completely removed, a mismatch is continually created and eventually, MutS, which a part of the DNA repair pathway, signals apoptosis in the cell. Magnetic resonance imaging (MRI) is firmly established as a diagnostic and assessment method for GBM patients, providing structural as well as functional (e.g. cerebral blood flow and volume, permeability) information. Positron emission tomography (PET) is a different imaging modality that offers complementary information about changes in tumor metabolism. Recently, a new method for efficient radiolabeling of TMZ was developed at the Martinos Center. This radiotracer ([11C]TMZ) can be used to monitor changes in TMZ distribution in the tumor during antiangiogenic treatment. Simultaneous MR-PET provides all the MRI-based metrics while imaging the delivery of [11C]TMZ to the tumor. Such data could be the means to provide answers to many important biomedical questions, including the very compelling question of how anti-angiogenic agents may be working. In this project, we will focus on the PET data analysis. This will include PET data processing, image reconstruction and pharmacokinetic analysis. The PET data were acquired for 90 minutes simultaneously with the MR data acquisition using the integrated Siemens 3T MR-BrainPET camera in GBM patients. As a first step, an MR-based attenuation map will be created using the widely available Statistical Parametric Mapping (SPM) software. Next, MR-based motion compensation will be performed to improve the PET data quantification. Motion correction will be applied separately to each of the dynamic frames before image reconstruction. The motion compensated images will be reconstructed using the OP-OSEM 3D algorithm. The reconstructed volume will consist of 153 slices with 256×256 pixels (1.25×1.25×1.25 mm3). Finally, spectral analysis will be used to study the pharmacokinetics of [11C]TMZ. This method is preferred for investigating radiolabeled drugs as opposed to the more constrained compartment model approaches (e.g. two tissue compartment models) as it better captures the heterogeneous nature of these tumors.

 

 

Trainee Research

CaNCURE provides trainees with a 6-month hands-on research experience and one-on-one mentoring by leading researchers in cancer nanomedicine.   Projects performed by current and past participants include:

Uptake and localization of nanoparticles in prostate and lung cancer cells as a function of time and nanoparticle type

Surface-targeting, ligand-switching nanoparticles for mitochondrial drug delivery in prostate cancer

Detection of low-level mutations in DNA obtained from cancer patients, using PCR and nano-PCR

Assessment of Atherosclerotic Changes using Ferumoxytol as MRI Contrast Agent

Co-delivery of antibiotics and topoisomerase inhibitors to overcome chemoresistance

Nano-plasmonic exosome (nPLEX) assays for exosome analysis and antibody validation

Pharmacokinetic analysis of changes in temozolomide distribution after antiangiogenic treatment of glioblastoma

In Vivo Treatment of Established HGSOC Line Using Novel Therapy

Radiotherapeutic synergism of thermogelling cisplatin-loaded polymers for cervical cancer treatment

Software with built-in neuroanatomy atlas provides insight into cancer treatment

Inhibiting DNA repair after nanoparticle-amplified radiation therapy

T1-weighted imaging of primary pancreatic adenocarcinoma using magnetic ferumoxytol nanoparticles

Biological mechanisms of gold nanoparticle-enhanced radiation therapy of prostate cancer

Analysis of DREAM and E2F1 Competition for Cell Cycle Promoters during G1.

Combined delivery of targeted liposomal chemotherapeutics and photodynamic therapy to treat pancreatic cancer

Assessment of atherosclerotic changes following neoadjuvant therapy using ferumoxytol as contrast imaging agent

Longitudinal assessment of tumor heterogeneity during immunotherapy for metastatic melanoma

Co-delivery of protective substrate and chemotherapy drugs via lipid Bilayer Mesoporous Silica Nanoparticles

Small T Antigen Effect on Mitotic Proteins B-Myb and FOXM1

Use of a Triblock Copolymer Hydrogel for Controlled Release of Cisplatin and BMN-673

PDT and PIT with Chemotherapy for Treatment of 3D Ovarian Cancer Nodules Under Flow and Static Conditions

Radiation enhancement in cancer cells using gold and gadolinium nanoparticles

Optimization of macrophage-targeted nanoparticles for positron emission tomography imaging in cancer

Nanoencapsulation of tyrosine kinase inhibitors and their effects on pathway inhibition

Erythropoietin improves antitumor immune response through reversal of the hypoxic tumor microenvironment

Soleil Doggett (Biology, '16) talks to her fellow peers about her research on oxygenating tumors to stimulate the anti-tumor immune response.

 

Trainee e-portfolios

Photo credit: Tom Kates Photography

While on co-op, trainees document their research in an e-portfolio.  This gives trainees the opportunity to provide regular updates on their research progress, reflect on training they are receiving, and explain how their research fits within the field of cancer nanomedicine.  These research e-portfolios can be accessed through individual trainee profiles.  The complete collection may be found here.

 

Presentation at CaNCURE Nanomedicine Day

At the completion of their co-op, trainees are provided with the opportunity to present their research to a wider audience.  For our June CaNCURE Nanomedicine Day, trainees prepare interactive, digital posters to display on electronic poster boards.  Over 100 faculty, students, and researchers attend this annual event!

Check out the news article about our first CaNCURE Day!

Trainee Publications

Our Trainees have published 22 peer-reviewed since January 2015.  A full list of Trainee publications is found below.

  1. Patrick Sheedy, Zdravka Medarova. The fundamental role of miR-10b in metastatic cancer. Am J Cancer Res 2018;8(9):1674-1688. Link
  2. Chen X, Ling X, Zhao L, Xiong F, Hollett G, Kang Y, Barrett A, Wu J. “Biomimetic Shells Endow Sub-50 nm Nanoparticles with Ultrahigh Paclitaxel Payloads for Specific and Robust Chemotherapy.”  ACS Appl Mater Interfaces. 2018 Sep 25. doi: 10.1021/acsami.8b11571. PMID: 30203956  Link
  3. Hedgire S, Krebill C, Wojtkiewicz GR, Oliveira I, Ghoshhajra BB, Hoffmann U, Harisinghani MG. “Ultrasmall superparamagnetic iron oxide nanoparticle uptake as noninvasive marker of aortic wall inflammation on MRI: proof of concept study.”   Br J Radiol. 2018 Sep 12:20180461. doi: 10.1259/bjr.20180461. PMID: 30160173  Link
  4. Application of the BLADE Sequence in Upper Abdominal MR Imaging. Krebill C.  Radiol Technol. 2018 May;89(5):495-497. PMID:29793909 Link
  5. Torrado-Carvajal A, Vera-Olmos J, Izquierdo-Garcia D1, Catalano OA, Morales MA, Margolin J, Soricelli A, Salvatore M, Malpica N, Catana C1. Dixon-VIBE Deep Learning (DIVIDE) Pseudo-CT Synthesis for Pelvis PET/MR Attenuation Correction. J Nucl Med. 2018 Aug 30. pii: jnumed.118.209288. doi: 10.2967/jnumed.118.209288. PMID: 30166357  Link
  6. Xiaoyuan Ji, Jie Wang, Lin Mei, Wei Tao, Austin Barrett, Zhiguo Su, Shaomin Wang. Guanghui Ma, Jinjun Shi, Songping Zhang. Artificial Photosynthesis: Porphyrin/SiO2 /Cp*Rh(bpy)Cl Hybrid Nanoparticles Mimicking Chloroplast with Enhanced Electronic Energy Transfer for Biocatalyzed Artificial Photosynthesis. Advanced Functional Materials. Link
  7. Yang KS, Im H, Hong S, Pergolini I, Del Castillo AF, Wang R, Clardy S, Huang CH, Craig Pille, Ferrone, Yang R, Castro CM, Lee H, Del Castillo CF, Weissleder R. Multiparametric plasma EV profiling facilitates diagnosis of pancreatic malignancy. Sci Transl Med. 2017; 9(391): eaal3226. PMC5846089
  8. Zhu X, Ji X, Kong N, Chen Y, Mahmoudi M, Xu X, Ding L, Tao W, Cai T, Li Y, Gan T, Austin Barrett, Bharwani Z, Chen H, Farokhzad OC. Intracellular Mechanistic Understanding of 2D MoS2 Nanosheets for Anti-Exocytosis-Enhanced Synergistic Cancer Therapy.  ACS Nano. 2018 Mar 27;12(3):2922-2938. PMC6097229
  9. Miller MA1, Kim E, Cuccarese MF, Alec Plotkin, Prytyskach M, Kohler RH, Pittet MJ, Weissleder R. “Near infrared imaging of Mer tyrosine kinase (MERTK) using MERi-SiR reveals tumor associated macrophage uptake in metastatic disease.” Chem Commun. 2017 Dec 19;54(1):42-45. PMC5736449
  10. Ding L, Zhu X, Wang Y, Shi B, Ling X, Chen H, Nan W, Austin Barrett, Guo Z, Tao W, Wu J, Shi X. “Intracellular Fate of Nanoparticles with Polydopamine Surface Engineering and a Novel Strategy for Exocytosis-Inhibiting, Lysosome Impairment-Based Cancer Therapy”. Nano Lett. 2017 Nov 8;17(11):6790-6801.  PMC6071871
  11. Yoo B, Ann-Marie, Billig, Medarova Z. “Guidelines for Rational Cancer Therapeutics. Frontiers in Oncology Journal”. Front Oncol. 2017 Dec 12;7:310. PMC5732930
  12. Gharagouzloo C, Timms L, Qiao J, Fang Z, Joseph Nneji, Pandya A, Kulkarni P, van de Ven AL, Ferris C, Sridhar S. “Neural circuits and brain function: New insights using quantitative vascular mapping of the rat.” Neuroimage, 2017. 16C:24-33  PMC5824692
  13. Gharagouzloo C, Timms L, Qiao J, Fang Z, Joseph Nneji, Pandya A, Kulkarni P, van de Ven AL, Ferris C, Sridhar S.   “Dataset on a 173 region awake resting state quantitative cerebral blood volume rat brain atlas and regional changes to cerebral blood volume under isoflurane anesthetization and CO2 challenge”. Data in Brief, 2018. 17:393-396.  Link
  14. Qin L, Li A, Qu J, Reinshagen K, Li X, Cheng S, Annie Bryant, Young GS. Normalization of ADC does not improve correlation with overall survival in patients with high-grade glioma (HGG). J Neurooncol. 2018 Apr;137(2):313-319.   PMC6071871
  15. Belz J, Kumar R, Baldwin P, Noelle Castilla Ojo, Leal AS, Royce DB, Di Zhang D, van de Ven AL, Liby K, Sridhar S. “Sustained-release Talazoparib implants for localized treatment of BRCA1-deficient breast cancer”. Theranostics, 7(17): 4340-4349.  PMC5695017
  16. Qin L, Li X, Amanda Stroiney, Qu J, Helgager J, Reardon DA, Young GS. “Advanced MRI assessment to predict benefit of anti-programmed cell death 1 protein immunotherapy response in patients with recurrent glioblastoma.” 2017 Feb;59(2):135-145.  PMC6097616
  17. Jodi Belz, Noelle Castilla Ojo,Srinivas Sridhar, Rajiv Kumar.  Radiosensitizing silica nanoparticles encapsulating docetaxel for treatment of prostate cancer, In Cancer Nanotechnology. Reema Zeineldin (Ed).  Series: Methods in Molecular Biology. Springer Press. Methods Mol Biol. 2017; 1530:403-409. PMC5531609
  18. Christian Berrios, Megha Padi, Mark A. Keibler, Donglim Esther Park, Vadim Molla, Gregory Stephanopoulos, John Quackenbush, James A. DeCaprio. “Merkel cell polyomavirus small T antigen promotes pro-glycolytic metabolic perturbations required for transformation”. 2016 Nov 23;12(11):e1006020.   PMC5120958
  19. Song C, Liu Y, Rachel Fontana, Makrigiorgos A, Mamon H, Kulke MH, G. Mike Makrigiorgos. “Elimination of unaltered DNA in mixed clinical samples via nuclease-assisted minor-allele enrichment”.  2016 Nov 2;44(19):e146. PMC5100565
  20. Andrew L. Hong, Yuen-Yi Tseng, Glenn S. Cowley, Oliver Jonas, Jaime H. Cheah, Bryan D. Kynnap, Mihir B. Doshi, Coyin Oh, Stephanie C. Meyer, Alanna J. Church, Shubhroz Gill, Craig M. Bielski, Paula Keskula, Alma Imamovic, Sara Howell, Gregory V. Kryukov, Paul A. Clemons, Aviad Tsherniak, Francisca Vazquez, Brian D. Crompton, Alykhan F. Shamji, Carlos Rodriguez-Galindo, Katherine A. Janeway, Charles W. M. Roberts, Kimberly Stegmaier, Paul van Hummelen,
Michael J. Cima, Robert S. Langer, Levi A. Garraway, Stuart L. Schreiber, David E. Root,
William C. Hahn, & Jesse S. Boehm. “Integrated genetic and pharmacologic interrogation of rare cancers”. Nat Commun. 2016 Jun 22;7:11987.  PMC4917959
  21. Wang P, Yoo B, Sherman S, Mukherjee P, Ross A, Pantazopoulos P, Petkova V, Farrar C, Medarova Z, Moore A. “Predictive imaging of chemotherapeutic response in a transgenic mouse model of pancreatic cancer.” Int J Cancer. 2016 Aug 1;139(3):712-8. PMCID: PMC4925171
  22. Nazila Kamaly, Gabrielle Fredman, Jhalique J. Fojas, Manikandan Subramanian, Won II Choi, Katherine Zepeda, Cristian Vilos, Mikyung Yu, Suresh Gadde, Jun Wu, Jaclyn Milton, Renata Leitao, Livia Rosa, Moaraj Hasan, Huayi Gao, Vance Nguyen, Jordan Harris, Ira Tabas, and Omid C. Farokhzad. “Interleukin-10 Targeted Nanotherapeutics Developed with a Microfluidic Chip Enhance Resolution of Inflammation in Advanced Atherosclerosis”. ACS Nano. 2016 May 24;10(5):5280-92. PMC5199136