Drug-chemo combo destroys challenging breast cancer stem cells

Gregg Semenza

Gregg Semenza

Researchers affiliated with Johns Hopkins Physical Sciences-Oncology Center (PS-OC) have shown that combining chemotherapy with an agent that blocks a certain cancer survival protein holds the key to fighting one of the the toughest forms of breast cancer.

Only 20 percent of patients with what are known as “triple-negative” breast cancer cells respond to chemotherapy. PS-OC associate director and Johns Hopkins professor of  medicine Gregg Semenza demonstrated in a recent study that chemotherapy actually enhances triple-negative cancer stem cell survival by switching on proteins called hypoxia-inducible factors (HIF). But when combined with currently available and FDA-approved HIF-inhibiting drugs, such as digoxin, Semenza said, chemotherapy shrank tumors.

Mice with implanted triple-negative breast cancer stem cells were treated with a combination therapy comprised of the HIF-inhibiting drug plus the chemotherapeutic drug paclitaxel. That combo treatment decreased tumor size by 30 percent more than treatment with chemotherapy. Furthermore, Semenza’s study showed that combining digoxin with the a different chemotherapeutic agent called gemcitabine “brought tumor volumes to zero within three weeks and prevented the immediate relapse at the end of treatment that was seen in mice treated with gemcitabine alone,” a press release on the study stated. Clinical trials will be needed to verify these results.

Debangshu Samanta, Ph.D., a postdoctoral fellow in the Semenza lab, was the lead author on this research published online in the Proceedings of the National Academy of Sciences. Additional authors include Daniele Gilkes, Pallavi Chaturvedi and Lisha Xiang of the Johns Hopkins University School of Medicine.

Read the PNAS article here.

Visit the PS-OC website here.

For all press inquiries regarding INBT, its faculty and programs, contact INBT’s science writer Mary Spiro, mspiro@jhu.edu or 410-516-4802.

 

Gerecht nets American Heart Association grant

Sharon Gerecht, associate professor in the Department of Chemical and Biomolecular Engineering and affiliated faculty member of Johns Hopkins Institute for NanoBioTechnology, has received the prestigious American Heart Association Established Investigator Award.

sharongerecht_cropThe AHA awarded only four such grants this year, funding designed to support mid-career of investigators who show unusual promise and accomplishments in the study of “cardiovascular or cerebrovascular science.”

Gerecht’s research focuses on engineering platforms, specifically hydrogels, that are designed to coax stem cells to develop into the building blocks of blood vessels. The hope is that these approaches could be used to help repair circulatory systems that have been damaged by heart disease, diabetes, and other illnesses.

Additionally, Gerecht leads a research project in the Johns Hopkins Physical Science-Oncology Center where she is studying the effects of low oxygen (hypoxia) on the tumor growth and blood vessel formation. The AHA funding will support her work on regulating hypoxia in hydrogels for vascular regeneration. The award is worth approximately $400,000 over five years.

Learn more about the Gerecht lab here.

For all press inquiries regarding INBT, its faculty and programs, contact INBT’s science writer Mary Spiro, mspiro@jhu.edu or 410-516-4802.

 

INBT’s fall student symposium Nov. 7

An important opportunity in graduate school is to get peer and mentor feedback on results. One of the best ways to do that is to share what you have been working on with your colleagues at a symposium.

Jordan Green

Jordan Green

Come hear the latest updates from Johns Hopkins Institute for NanoBioTechnology’s research centers on Friday, November 7 from 9 a.m. to 12:30 p.m. in the Great Hall at Levering on the Homewood campus! Students affiliated with laboratories from the Johns Hopkins Physical Sciences-Oncology Center, Johns Hopkins Center of Cancer Nanotechnology Excellence and INBT will present at this student-organized symposium. This event is free and open to the Johns Hopkins community. Refreshments provided.

The keynote faculty speaker is Jordan Green, associate professor at Johns Hopkins Department of Biomedical Engineering. Green was recently named one of Popular Science magazine’s “Brilliant 10.” Breakfast, networking and introductions begin at 9 a.m.

Student speakers and topics include:
**Kristen Kozielski – Bioreducible nanoparticles for efficient and environmentally triggered siRNA delivery to primary human glioblastoma cells. Jordan Green Lab. 9:30-9:45 a.m.

**Angela Jimenez – Spatio-temporal characterization of tumor growth and invasion in three-dimensions (3D). Denis Wirtz Lab. 9:50-10:05 a.m.

**Amanda Levy – Development of an in vitro system for the study of neuroinflammation. Peter Searson Lab. 10:10- 10:25 a.m.

**Max Bogorad – An engineered microvessel platform for quantitative imaging of drug permeability and absorption.  Peter Searson Lab. 10:30-10:45 a.m.

**Greg Wiedman – Peptide Mediated Methods of Nanoparticle Drug Delivery. Kalina Hristova Lab. 10:50 to 11:05 a.m.

**Jordan Green – Particle-based micro and nanotechnology to treat cancer 11:10 a.m. – 12:10 p.m.

Please RSVP on our Facebook event page here.

For all press inquiries regarding INBT, its faculty and programs, contact Mary Spiro, mspiro@jhu.edu or 410-516-4802.

Boarding the research bandwagon

The story of how I joined Johns Hopkins Institute for NanoBioTechnology (INBT) is actually one of those moments where it just hits you – Why haven’t I thought about doing this before? It started with me being back at home during the winter of my sophomore year, meeting friends of my parents and answering the most common question: Where do you study? One of the reactions that stuck with me the whole night was “Wow, how does it feel to be in the center of the most cutting-edge research?” This made me realize how I’d been oblivious to one of the things I would love to get involved in.

Better one and a half years late than never, I decided to join the research bandwagon as well. I started going through the profiles of labs on Homewood campus, looking for a topic that would make me want to be there in lab every free minute during the year. I finally found one that sparked my curiosity: the Denis Wirtz Lab. Dr. Wirtz is the Smoot Professor in the Department of Chemical and Biomolecular Engineering and also the University’s Vice Provost for Research.

IMG_0161

Working in the lab!

Though at the time most of the stuff I read about the Wirtz lab went over my head, I knew that cancer was something I had always wanted the world to be rid of. Seeing near and dear ones succumb to it was one of the most excruciating things which I wanted no one to experience in the future. Fascinated by the approach taken by Dr. Wirtz, I shot him off an email and to my amazement, I got an email back within the hour, “Sent to my grad students, look forward to working with you. d”. The next day I was scheduled to be back in Baltimore, and the day after that, I was a part of Wirtz lab.

During my training, I remember asking one of my peers “How in the world can I remember all these procedures, let alone do them?” She simply smiled and said, “You’ll see”. In a few weeks, I found myself doing those very procedures, one step after another as if it were a reflex action. I would most definitely attribute me being able to do this to my grad student Hasini Jayatilaka (don’t kill me for calling you out!). At the end of the day, what I felt it boiled down to, was realizing that the person I work for was in the same shoes five-seven years ago as I was now, and she wouldn’t expect anything unrealistic out of me. Once you embrace the challenge ahead, knowing that there is no need to be intimidated, you’re good to go.

The best part of being involved in research, apart from the work you do, is sitting in class in a lecture hall and suddenly tune in to the professor talking about something that you do in lab each day. That moment cements your understanding of why you did what you’ve been doing for so many days, it connects the dots in your mind, and that moment is when you’ve completed the full circle between theory and practice.

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Our team at a poster presentation over the summer.

For me personally, having to come to lab got me into a disciplined schedule. I had a fixed time for all days of the week now to wake up (which for me used to be the latest possible time before), since if I had no morning classes, I was in lab. It helped me a lot with my time management skills, with me cutting down on TV shows and sporadic naps. To my surprise, it did not affect the amount of time I spent with my friends, as the reduction in TV shows and naps was (extremely) disturbingly enough to keep every other aspect of my daily schedule the same. Being surrounded in lab by people in similar academic disciplines also gets me a ton of advice on classes. It’s like my own little “rate-my-professor” that encourages me to definitely take some class if it is “the best class I will take at Hopkins”. At times, it’s also a ‘learning den’ where I can get help with classes if I need to. Getting involved in a research lab also came with social outings with the team, with our dinners enabling us to get to know each other on a more personal level. I feel that this in a big way contributed to the chemistry we have while working with each other, made us comfortable spending time with each other at work.

At this point, after nine exciting months, including a fully lab-packed summer, I feel that this continues to be one of the best decisions I made so far. I do not regret being here every day, but take pride in saying “I need to be in lab”. One of the most cherished take-away for me is developing a sense of accountability for my actions, which I feel is an important aspect in life. I would definitely encourage being involved in research while at Hopkins as you have nothing to lose but so much to gain.

Pranay Tyle, is a junior in Chemical and Biomolecular Engineering minoring in Economics, and hopes to one day manufacture low cost medicine accessible to those in dire need across the globe.

For all press inquiries regarding INBT, its faculty and programs, contact Mary Spiro, mspiro@jhu.edu or 410-516-4802.

Veltri presents PS-OC hosted talk on digital pathology and prostate cancer

Robert Veltri, associate professor Of Urology and Oncology at the Johns Hopkins School of Medicine and Director of the Fisher Biomarker Biorepository Laboratory, will  present the talk Quantitative Histomorphometry of Digital Pathology: Case study in prostate cancer,” to members of the Denis Wirtz Lab and the Johns Hopkins Physical Sciences-Oncology Center on Monday, December 9 at 2 p.m. in Croft G40 on the Homewood campus. Seating is limited.

veltri

Robert Veltri

Veltri studies the biomarkers for prostate and bladder cancer and is collaborating on applications of Quantitative Digital Image Analysis (QDIA) using microscopy to quantify nuclear structure and tissue architecture. Collaborations include Case Western Reserve University biomedical engineering and the University of Pittsburgh Electrical Engineering departments studying to assess cancer aggressiveness in prostate cancer (PCa). Furthermore,  he is studying the application of molecular biomarkers for prostate (CaP) and bladder cancer (BlCa) detection and prognosis. Veltri’s work is funded by the National Cancer Institute’s PS-OC program grant), Early Detection Research Network (EDRN), and the Department of Defense related to research on Active Surveillance for PCa. He is also a co-investigator on a SBIR-I and II grant studying the application of microtransponders to multiplex molecular urine and serum biomarker testing for CaP.  Veltri has authored over 152 scientific publications and is either inventor or co-inventor on over twenty patents and two trademarks.

Veltri presents PS-OC hosted talk on digital pathology and prostate cancer

Robert Veltri, associate professor Of Urology and Oncology at the Johns Hopkins School of Medicine and Director of the Fisher Biomarker Biorepository Laboratory, will  present the talk Quantitative Histomorphometry of Digital Pathology: Case study in prostate cancer,” to members of the Denis Wirtz Lab and the Johns Hopkins Physical Sciences-Oncology Center on Monday, December 9 at 2 p.m. in Croft G40 on the Homewood campus. Seating is limited.

veltri

Robert Veltri

Veltri studies the biomarkers for prostate and bladder cancer and is collaborating on applications of Quantitative Digital Image Analysis (QDIA) using microscopy to quantify nuclear structure and tissue architecture. Collaborations include Case Western Reserve University biomedical engineering and the University of Pittsburgh Electrical Engineering departments studying to assess cancer aggressiveness in prostate cancer (PCa). Furthermore,  he is studying the application of molecular biomarkers for prostate (CaP) and bladder cancer (BlCa) detection and prognosis. Veltri’s work is funded by the National Cancer Institute’s PS-OC program grant), Early Detection Research Network (EDRN), and the Department of Defense related to research on Active Surveillance for PCa. He is also a co-investigator on a SBIR-I and II grant studying the application of microtransponders to multiplex molecular urine and serum biomarker testing for CaP.  Veltri has authored over 152 scientific publications and is either inventor or co-inventor on over twenty patents and two trademarks.

Game Theory and Cancer

What does game theory and cancer have to do with each other. I am not sure but this interesting workshop hosted by the Princeton Physical Sciences-Oncology Center and Johns Hopkins University might help you figure that out.

An announcement about the event reads:

Screen Shot 2013-08-02 at 12.03.06 PMRegistration is now open for the Workshop on Game Theory and Cancer, scheduled on August 12-13 in Baltimore, MD, and jointly hosted by our Princeton PS-OC and Johns Hopkins University. The main goal of this workshop is to provide a dialogue between leading basic researchers and clinical investigators that would help make headway against the very stubborn problem of cancer, and to jolt the oncology community into confronting the serious clinical problems that have previously been avoided.

The flyer is pretty cool, too.  Check it out here.

Additional information and preliminary agenda can be found at: http://www.princeton.edu/psoc/training/

To register, please go to: https://prism.princeton.edu/ps-oc/regform.php

For questions about the event, email maranzam@princeton.edu or sclam@princeton.edu

Lab coats are summer gear for high school researchers

You don’t think of a lab coat as summer wear for teens, but we don’t quite feel like it’s summer around here until our research interns have arrived. Early in June, INBT’s undergraduate nano-bio researchers arrived. This week our high schoolers in the Summer Academic Research Experience (SARE) scholars got started.

SARE pairs specially selected teens with university mentors who guide them through a mini research project. At the end of their time here, they hold a small poster session. The students gain valuable work skills, learn about scientific careers, get tutoring help, practice their writing, gather data for their projects and earn some cash for the future. Students in the program are recruited from the Boys Hope Girls Home of Baltimore program, The SEED School of Maryland and The Crossroads School, all of which assist in differing ways with in the education, housing, tutoring  and counseling of promising young people from disadvantaged circumstances.

The SARE program was launched in 2009 by Doug Robinson, professor in the cell biology department at the School of Medicine, and is funded jointly by the medical school and Johns Hopkins Institute for NanoBioTechnology.

This year’s SARE scholars include: Diana Bobb is being mentored by Makoto Tanigawa in the Takanari Inoue Lab in the Department of Cell Biology; Kaleel Byrd is being mentored by Ryan Vierling in the Caren Meyers Lab in the Department of Pharmacology; Milan Dower is being mentored by Tom Lampert in the Peter Devreotes Lab in the Department of Cell Biology; Jewel Herndon is being mentored by Herschel Wade in his lab in the Department of Biophysics; De’Sean Markley is being mentored by Hoku West-Foyle in the Douglas Robinson Lab in the Department of Cell Biology

Fraley nets $500K Burroughs Wellcome Fund award for microfluidics work

Stephanie Fraley (Photo: Homewood Photography)

Stephanie Fraley (Photo: Homewood Photography)

A Johns Hopkins research fellow who is developing novel approaches to quickly identify bacterial DNA and human microRNA has won the prestigious $500,000 Burroughs Wellcome Fund (BWF) Career Award at the Scientific Interfaces. The prize, distributed over the next five years, helps transition newly minted PhDs from postdoctoral work into their first faculty positions.

Stephanie Fraley is a postdoctoral fellow working with Samuel Yang, MD, in Emergency Medicine/Infectious Disease at the Johns Hopkins School of Medicine and Jeff Wang, PhD, in Biomedical Engineering with appointments in the Whiting School of Engineering and the medical school. The goal of her work is to develop engineering technologies that can diagnose and guide treatment of sepsis, a leading cause of death worldwide, while simultaneously leading to improved understanding of how human cells and bacterial cells interact.

“Sepsis is an out of control immune response to infection,” Fraley said. “We are developing tools that are single molecule sensitive and can rapidly sort and detect bacterial and host response markers associated with sepsis. However, our devices are universal in that they can be applied to many other diseases.”

Fraley is using lab-on-chip technology, also known as microfluidics, to overcome the challenges of identifying the specific genetic material of bacteria and immune cells. Her technology aims to sort the genetic material down to the level of individual sequences so that each can be quantified with single molecule sensitivity.

“Bacterial DNA is on everything and contamination is everywhere, so trying to find the ones associated with sepsis is like the proverbial search for the needle in the haystack,” Fraley said. “With microfluidics, we can separate out all the bacterial DNA, so instead of a needle in a haystack, we have just the needles.”

Another advantage to Fraley’s novel technology is that it will assess all the diverse bacterial DNA present in a sample, without presuming which genetic material is important. “Bacteria are constantly evolving and becoming drug resistant,” she said. “With this technology, we can see all the bacterial DNA that is present individually and not just the strains we THINK we need to look for.”

Fraley’s award will follow her wherever her career takes her. The first two years of the prize fund postdoctoral training and that last three years help launch her professional career in academia. During the application process, she had to make a short presentation on her proposal to BWF’s panel of experts. “It was like the television show ‘Shark Tank’ but for scientists,” she laughs. “ The panelists gave me many helpful suggestions on my idea.”

Fraley earned her bachelor’s degree in chemical engineering from the University of Tennessee at Chattanooga and her doctorate in chemical and biomolecular engineering with Denis Wirtz, professor and director of Johns Hopkins Physical Sciences-Oncology Center. Wirtz is associate director for the Institute for NanoBioTechnology and Yang and Wang also are INBT affiliated faculty members.

BWF’s Career Awards at the Scientific Interface provides funding to bridge advanced postdoctoral training and the first three years of faculty service. These awards are intended to foster the early career development of researchers who have transitioned or are transitioning from undergraduate and/or graduate work in the physical/mathematical/computational sciences or engineering into postdoctoral work in the biological sciences, and who are dedicated to pursuing a career in academic research. These awards are open to U.S. and Canadian citizens or permanent residents as well as to U.S. temporary residents.

Landmark physical characterization of cancer cells completed

An enormous collaborative effort between a multitude of academic and research centers has characterized numerous physical and mechanical properties on one identical human cancer cell line. Their two-year cooperative study, published online in the April 26, 2013 journal Science Reports, reveals the persistent and agile nature of human cancer cells as compared to noncancerous cells. It also represents a major shift in the way scientific research can be accomplished.

Human breast cancer cells like these were used in the study. (Image created by Shyam Khatau/ Wirtz Lab)

Human breast cancer cells like these were used in the study. (Image created by Shyam Khatau/ Wirtz Lab)

The research, which was conducted by 12 federally funded Physical Sciences-Oncology Centers (PS-OC) sponsored by the National Cancer Institute, is a systematic comparison of metastatic human breast-cancer cells to nonmetastatic breast cells that reveals dramatic differences between the two cell lines in their mechanics, migration, oxygen response, protein production and ability to stick to surfaces. They have also discovered new insights into how human cells make the transition from nonmalignant to metastatic, a process that is not well understood.

Denis Wirtz, a Johns Hopkins professor of chemical and biomolecular engineering with joint appointments in pathology and oncology who is the corresponding author on the study, remarked that the work adds a tremendous amount of information about the physical nature of cancer cells. “For the first time ever, scientists got together and have created THE phenotypic signature of cancer” Wirtz said. “Yes, it was just one metastatic cell line, and it will require validation with many other cell lines. But we now have an extremely rich signature containing many parameters that are distinct when looking at metastatic and nonmetastatic cells.”

Wirtz, who directs the Johns Hopkins Physical Sciences-Oncology Center, also noted the unique way in which this work was conducted: all centers used the same human cell line for their studies, which makes the quality of the results unparalleled. And, since human and not animal cells were used, the findings are immediately relevant to the development of drugs for the treatment of human disease.

“Cancer cells may nominally be derived from the same patient, but in actuality they will be quite different because cells drift genetically over just a few passages,” Wirtz said.  “This makes any measurement on them from different labs like comparing apples and oranges.” In this study, however, the genetic integrity of the cell lines were safeguarded by limiting the number times the original cell cultures could be regrown before they were discarded.

The nationwide PS-OC brings together researchers from physics, engineering, computer science, cancer biology and chemistry to solve problems in cancer, said Nastaran Zahir Kuhn, PS-OC program manager at the National Cancer Institute.

“The PS-OC program aims to bring physical sciences tools and perspectives into cancer research,” Kuhn said. “The results of this study demonstrate the utility of such an approach, particularly when studies are conducted in a standardized manner from the beginning.”

For the nationwide project, nearly 100 investigators from 20 institutions and laboratories conducted their experiments using the same two cell lines, reagents and protocols to assure that results could be compared. The experimental methods ranged from physical measurements of how the cells push on surrounding cells to measurements of gene and protein expression.

“Roughly 20 techniques were used to study the cell lines, enabling identification of a number of unique relationships between observations,” Kuhn said.

Wirtz added that it would have been logistically impossible for a single institution to employ all of these different techniques and to measure all of these different parameters on just one identical cell line. That means that this work accomplished in just two years what might have otherwise taken ten, he said.

The Johns Hopkins PS-OC made specific contributions to this work. Using particle-tracking microrheology, in which nanospheres are embedded in the cell’s cytoplasm and random cell movement is visually monitored, they measured the mechanical properties of cancerous versus noncancerous cells. They found that highly metastatic breast cancer cells were mechanically softer and more compliant than cells of less metastatic potential.

Using 3D cell culturing techniques, they analyzed the spontaneous migratory potential (that is, migration without the stimulus of any chemical signal) of cancerous versus noncancerous cells. They also analyzed the extracellular matrix molecules that were deposited by the two cell lines and found that cancerous cells deposited more hyaluronic acid (HA). The HA, in turn, affects motility, polarization and differentiation of cells.  Finally, the Hopkins team measured the level of expression of CD44, a cell surface receptor that recognizes HA, and found that metastatic cells express more CD44.

The next steps, Wirtz said, would be to validate these results using other metastatic cell lines.  To read the paper, which is published in an open access journal, follow this link: http://www.nature.com/srep/2013/130422/srep01449/full/srep01449.html

Excerpts from original press release by Princeton science writer Morgan Kelly were used.