Research Highlight


A patient with a tumor in the left inguinal lymph node, near the spine. After being imaged via PET/CT, the separate PET and CT images are combined to generate a single PET/CT (bottom) image, which measures the location and metabolic activity within tumors in one setting.

Longitudinal assessment of tumor heterogeneity during immunotherapy for metastatic melanoma

Melanoma is an aggressive form of skin cancer that develops from genetic changes in melanocytes, the pigment producing cells in the epidermal layers of skin. Traditional treatments for melanoma include surgery, radiation therapy, and systemic therapy. Patients with early stages of melanoma have a 90% survival rate over 5 years in the United States. However, patients with advanced melanoma, where the tumor has metastasized to other parts of the body, only have a 10% survival rate over 5 years and less than 25% of patients survive for longer than 1 year. Thus, novel targeted treatment approaches like immunotherapy are being investigated in medical research and clinical trials to improve the survival rates of patients with metastatic melanoma. In this investigation, patients with metastatic melanoma were treated with a novel immunotherapeutic agent and the metabolic activity of their tumors was measured using Positron Emission Tomography Computed Tomography (PET/CT) imaging, before, during and after the induction dose of the immunotherapy. PET/CT was used to measure changes in tumor characteristics (e.g. size and metabolic activity) during the course of the therapy. These patients were also monitored after the end of therapy to evaluate their clinical outcome (e.g. remission, progression, or recurrence of their disease) and survival rates. The PET/CT images of these patients will be analyzed to assess how the tumor characteristics changed in response to the immunotherapy, and to observe variations or heterogeneity. The heterogeneity of metabolic activity within and between the tumors in the same patient, and in the cohort of patients will be measured during this analysis. The immunotherapeutic agent was a monoclonal antibody that targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), a protein receptor found on the surface of activated T cells. CTLA-4 acts as a brake for the immune system. When CTLA-4 binds to ligands on the surface of melanoma cells, it downregulates the activation of T cells and prevents the immune system from destroying the tumors. The monoclonal antibody specifically binds to CTLA-4 and inhibits the function of the bound protein molecule, thus boosting the immune system’s response to the tumors. Oncologists routinely use imaging throughout traditional treatment to observe the effects of treatment and determine the next course of action. When melanoma cells are killed by the immune system during immunotherapy, changes in the characteristics of the metastatic tumors may be observed with PET/CT imaging, which provides two complementary components of tumor characterization that are important for monitoring the cytotoxic effect of immunotherapy. PET measures metabolic activity within tumor cells with high sensitivity but has limited spatial resolution, while CT provides high resolution anatomical imaging but cannot differentiate between active and dead tumor tissue. Therefore, combined PET/CT imaging measures location and metabolic activity within tumors in one setting. For PET/CT imaging, patients were injected with the glucose analog 18F-fluorodeoxyglucose (18F-FDG) to measure metabolic activity of their tumors. As a glucose analog, 18F-FDG is transported into cells that require glucose as an energy source. Cancer cells tend to use more glucose than cells in the surrounding tissue (the Warburg effect), so tumors uptake more 18F-FDG and appear as hyperintense regions in PET/CT images. When the 18F undergoes nuclear decay, it emits a positron, a positively-charged particle with the mass of an electron. Emitted positrons travel a very short distance before interacting with an electron and annihilating, releasing two gamma rays that travel in opposite directions. PET detects these pairs of annihilation gamma rays and pinpoints the location and quantity of 18F-FDG within the tumor and surrounding tissues, while CT provides the anatomical reference for the location of the detected 18F-FDG signals.

 

 

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:

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

Development of PSMA-targeting nanoparticles for positron emitting tomography imaging in prostate cancer using animal models

Synthesis of DFO-Lys(PEG30k)-Cys(Cy3) to examine macropinocytosis in human and mouse cancers in vitro

Development of Smart INCeRT Brachytherapy Spacers via PLGA and Docetaxel for Combined Chemo-Radiation Therapies in Prostate Cancer

Expression of anti-apoptotic proteins in pancreatic cancers: A potential barrier to photodynamic killing

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

Targeted Delivery of Liposomes using PARP Inhibitors to Treat Non-Small Cell Lung Cancer

Molecular Analysis of Plasma Vesicles for Early Pancreatic Cancer Detection

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

Localized chemo- and chemo-radiation for the treatment of prostate cancer

Digital diffraction diagnostics for lymphoma and HPV

Protein-encapsulated nanoparticles for oral delivery of anti-mitotic agents in prostate cancer

Online monitoring and image-guided treatment of chemoresistant micrometastases

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

Discovering the Genetic Mechanism of Enhanced Metastatic Colonization in SMAD4 Mutant Tumors

Targeting WASp using Wiskostatin-gold nanoparticles

Quantification of SPION accumulation in tumors using positive-contrast MRI

Delivery of Titanium Dioxide Nanoparticles via Biodegradable PLGA Dissolving Microneedles for Sustainable Release

Development of a novel nanogel for non-invasive transdermal delivery of cancer vaccines using hyaluronic acid

Codelivery of tumor suppressor mRNA and anti-cancer drug in cancer treatment

Longitudinal assessment of tumor heterogeneity during immunotherapy for metastatic melanoma

Identifying genomic and compound dependencies in undifferentiated sarcomas

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

Investigating the use of Feraheme to monitor the immune response by PET in general inflammation and specific immune cell populations

Assessing sufficiency of the Tip60/p400 complex in inducing transcription of Merkel Cell Polyomavirus Small T antigen target genes.

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