Prostate Cancer Foundation Young Investigators Advance Cancer Research at the 2013 AACR in Washington DC
April 15, 2013—Each year hordes of cancer researchers come from the four corners of the world to an annual meeting hosted by the American Association for Cancer Research (AACR) held this year in Washington, DC. The idea is simple: share knowledge about how to prevent and cure cancer. Founded in 1907, AACR is one of the world’s largest scientific meetings, and the organization publishes eight (the newest, Cancer Immunology Research, just launched this month with a preview issue) peer-reviewed journals. This year’s AACR theme was Personalizing Cancer Care.
Amongst the brainiac throngs, Nobel laureates intermingle with young scientists, hashing out cancer dilemmas; seasoned researchers exchange informal odds-on bets over who will go on to join that ultra-exclusive Nobel club; biotech companies give tutorials on their technologies, such as how to catch and capture tumor cells circulating freely in the bloodstream so they can be tested for mutations or drug sensitivity; and session after session of data is presented and shared and questions are asked, answered or put out to the research world as “need more data here,” so get on the stick research folks. The printed research program is roughly the size of a New York City phone book, numbering 1,532 pages! of who is presenting what data on which cancer or cancer-causing biology. And when it comes to data presentations relevant to prostate cancer research, it can be as difficult to find a session that does not have a Prostate Cancer Foundation-funded researcher attached as it is to find a glacier in the Florida Keys.
This year, AACR presentations related to prostate cancer were chock full of Prostate Cancer Foundation Young Investigators—an elite group that now includes 120 young woman and men whose innovative scientific minds are breaking ground in the fight against prostate cancer. Dr. Soule, the chief science officer of the Prostate Cancer Foundation along with other Foundation staff met with about 20 Young Investigators (YIs) at AACR for lively interactive discussions of their work, the work of others and progress in the field. “We at PCF are so proud of the fantastic progress these amazing young scientific minds are contributing towards curing prostate cancer,” said Dr. Soule. Later, at the annual drinks party hosted by the AACR for attendees, more than one young investigator marveled over flatbread and wine that Soule somehow kept abreast of every single thing each YI was working on—almost like a proud papa.
We’ve selected a handful of PCF YIs who attended this year’s meeting and share their latest research with you along with a glimpse into what makes each of these cancer researchers tick.
Hung-Ming Lam, PhD
Dr. Lam, of the University of Washington in Seattle, is definitely not loud and boisterous but her science is, giving the research community clues into understanding how cancer recurs in patients. She is the first author on a poster titled “Disseminated Tumor Cell Heterogeneity and Dormancy in Prostate Cancer.” Prostate cancer can become lethal when it metastasizes to sites—mostly bone—outside of the primary tumor. But in some cases itinerant prostate cancer cells that have moved into bone remain dormant for years, not causing metastatic disease in the bone. Such dormancy can last one, five or even ten or more years—a significant time frame for a disease that strikes a primarily elderly population. Thus knowing what characteristics and genomic profiles occur in disseminated tumor cells (DTCs) will identify the rabble-rousing cells likely to cause metastatic tumors vs. the meek and quiet wallflower DTCs that are likely to remain dormant. Such knowledge may allow scientists to find ways to promote inactivity, or quiescence, in disseminated tumor cells or thwart metastatic conversion.
If DTCs can be kept in an inactive state for prolonged periods of time, many men might avoid having their lifespans shortened by prostate cancer. Dr. Lam and colleagues have identified a subset of candidate genes that predict cancer-promoting activity in DTCs. PCF-funded Dr. Peter Nelson is also an author on this poster.
Apart from her work, Dr. Lam was particularly excited about the N=1 session chaired by PCF-funded Dr. Charles Sawyers. (In scientific study, N is the number of patients studied; so for example if 208 men with prostate cancer were evaluated, that would be expressed as N=208 in scientific jargon. N=1 is study brought down to the level of individual personalization—one person studied.)
“Now, almost all of us agree that cancer is a very heterogeneous disease that involves interplay between cancer cells [that often harbor many different mutations] and the tumor microenvironment,” says Dr. Lam. “This year at AACR, I am especially fascinated about novel targets to the tumor microenvironment and cancer cells themselves. Every patient has a different makeup of these two components and these two components can be very different in various organs of the same patient. I totally agree that personalized medicine—per the N=1 session chaired by Dr. Charles Sawyers--is becoming realistic with the advancing diagnosis methods,” she said.
This N=1 issue was a hot topic at the conference with the editors of The Scientist reporting on these two competing quotes regarding the publishing of N=1 studies:
Obviously we’re not going to cure patients 1 by 1. . . . How can we go beyond the anecdote?
—Andrea Califano, Columbia University, on N of 1 trials
I would like to shame the editors of journals in the audience who think that N of 1 is an anecdote.
—Charles Sawyers, Memorial Sloan-Kettering Cancer Center, on the difficulty getting N of 1 trials published
Christopher Maher, PhD
Dr. Maher is quick with a grin, is disinclined to sit still and likes to talk about science as evidenced by the fact that he’s given 20 presentations since his Young Investigator Award in 2010. At this year’s AACR, Maher was a presenter and the chairperson of a session titled: “Next-generation Sequencing and Analysis of Genomes.” He also was an author on three separate poster data presentations. One—“Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer”—presented data on how particular enzymes can work in tandem to set cancer in motion. A second—“Patient-derived xenografts from advanced luminal-type breast cancer: insights into endocrine therapy resistance”—looked at how tumors develop resistance to endocrine therapies used to treat certain breast cancers. And the third—“The role of microRNA-101 as a master tumor suppressor in cancer”—presented data showing that a particular type of microRNA is down-regulated (less is produced than needed) in many cancers. This is an important clue because restoring this particular microRNA may prevent tumor progression.
When asked what his YI award meant to his career, Maher is not shy saying that the award fosters far more than just a research project. “Ultimately, it has enabled me to start my own independent laboratory.”
True to his natural buoyancy, Maher is an avid runner and travels to do so: “I’ve been crossing off states where I’ve run half or full marathons,” he says.
Read more about Dr. Maher and his work here
Amina Zoubeidi, MSc, PhD
The first noticeable feature of Dr. Zoubeidi is her infectious smile; the second is the intensity of her gaze. She is fully engaged. It’s hard to imagine her sleeping—ever. A native of Morocco, Dr. Zoubeidi, eschewed traditional cultural distaff paths and embarked on her scientific journey. She is mentored by PCF-funded Dr. Martin Gleave at the Vancouver Prostate Centre and speaks Arabic, French and English. When she does sleep—she must, really—one wonders what language she dreams in. Judging from her prolific work at the AACR, it’s probably science speak.
Dr. Zoubeidi, along with colleagues, presented three abstracts at AACR this year.
- Hsp27 is an essential effector of EGF-induced epithelial to mesenchymal transition in prostate cancer
Zoubeidi is the senior author on this poster presentation. Heat shock proteins (Hsp) are a class of proteins that become especially active when cells are stressed or exposed to attack from anti-cancer therapies. A specific heat shock protein, known as Hsp27, has multiple functions in the body, one of which is to “chaperone” or assist certain proteins that are implicated in cancer cell survival, especially under stress conditions. Hsp27 is overexpressed in lethal forms of prostate cancer. Also overexpressed is another protein known as EGF and EGFR; this occurs as prostate cancer advances to its most lethal form—treatment resistant prostate cancer. Zoubeidi and colleagues now demonstrate that Hsp27 and EGF proteins both play a role in driving the epithelial cells involved in prostate cancers towards a more chaotic state known as epithelial to mesenchymal transition, or EMT. (Normally as humans develop our cells move from a more embryonic state—mesenchymal—towards a more adult cell state—epithelial. Adult prostate cells are normally in the epithelial state, but as cells turn cancerous, a transition towards the embryonic mesenchymal state occurs.)
Zoubeidi et al also show that using the investigational drug OGX-427, currently undergoing Phase II clinical trials in men with treatment-resistant prostate cancer, they were able to reduce metastatic cancer progression in mice models of the disease. And because the data from Phase I clinical trial of OGX-427 showed a decrease in circulating tumor cells in patients with metastatic treatment-resistant prostate cancer, this study defines Hsp27 as a critical regulator of EMT and validates this chaperone as a therapeutic target to treat metastatic prostate cancer.
Two other PCF-funded researchers are also authors on this poster: Martin Gleave and Jennifer Bishop, the latter is being mentored by Zoubeidi and Gleave and is a newly minted 2013 PCF Young Investigator in an example of the virtous cycle the YI program fosters: YI to mentor in just about two years’ time.
- In another poster—“Mechanisms of resistance to enzalutamide in LNCaP models”—Zoubeidi as senior author and colleagues, including PCF-funded Martin Gleave, are investigating ways in which prostate cancer cells become resistant to anti-androgen drugs.
- And in a third poster presentation—“Clusterin downregulation sensitize prostate cancer cells to taxane by modulating mitosis”—Zoubeidi and colleagues give evidence on how a protein (Clusterin) can be downregulated by a drug that is in Phase III clinical trials (OGX-O11). This downregulation of Clusterin can make prostate cancer cells more sensitive to chemotherapy treatment commonly used to treat advanced cancers. PCF-funded researchers Martin Gleave was the senior author on this poster.
Zoubeidi has two main dreams, she says. First: finding that drug that will end prostate cancer suffering, and second, having enough money to buy all the shoes and pocketbooks she now can only drool over as she window shops. So evidently she does sleep, and when she does she’s definitely sporting Prada.
Read more about Zoubeidi and her work here.
Scott Tagawa, MD
Dr. Tagawa is a busy physician/scientist and it shows. He carries the look of a man who knows the names of the men with prostate cancer who need help and fast from doctors and researchers like him. He’s hyper-responsive to email entreaties from the Prostate Cancer Foundation, a trait he surely extends to his patients as well. Since his YI award in 2008 Tagawa has presented his research at large annual scientific meetings such as ASCO, AUA, AACR as well as the Genitourinary Cancers Symposium and the IMPaCT meeting which is sponsored by the Department of Defense. He’s also a regular presenter at the annual Prostate Cancer Foundation’s Annual Scientific Retreat.
Tagawa was an author on 4 posters presented at AACR this year.
- Non-invasive measurement of prostate-specific membrane antigen (PSMA) expression with radiolabeled J591 imaging: a promising biomarker for PSMA-based radioimmunotherapy
J591 is a man-made monoclonal antibody that is able to recognize a protein antigen (PSMA) expressed on virtually all prostate cancer cells, and more so in men with treatment-resistant metastatic disease. When a tiny tag of radioactive material is attached to the J591 antibody, that specifically targets prostate cancer cells, and delivered systemically this is known as radioimmunotherapy. Dr. Tagawa has been conducting clinical trials of the precision radioimmunotherapeutic J591 to determine its ability to eradicate prostate cancer cells that have metastasized. In this poster presentation, Tagawa and colleagues performed a combined analysis of four clinical studies of this radioimmunotherapeutic that examined 130 patients with metastatic treatment-resistant prostate cancer. They found that the levels of PSMA expression—as determined by a non-invasive scan--can be used to indicate response to their radioimmunotherapy.
- ERG induces taxane resistance in castration-resistant prostate cancer
Tagawa, along with five other Prostate Cancer Foundation-funded researchers, authored this paper. Taxanes are a type of chemotherapy drug that are used to treat advanced prostate cancer; however, inevitably prostate cancer patients develop resistance to these chemotherapy drugs. In this poster, Tagawa et al demonstrate that a genetic abnormality (ERG positivity) found in half of all men with prostate cancer plays an active role in inducing resistance to taxane-based chemotherapeutics. Additionally they’ve determined that men with ERG positive tumors have upregulation of another protein (clusterin) that can cause resistance to taxane chemotherapeutics. This work dovetails nicely with Dr. Zoubeidi’s work (see above) and shows the potential to use a drug now in clinical trials (OGX-011) to enhance response to chemotherapy in men whose prostate cancer is positive for the ERG genetic aberration.
- Using CTCs to interrogate mechanisms of taxane resistance in the prospective TAXYNERGY clinical trial in prostate cancer
This poster describes a prospective, randomized multi-site clinical trial that will enroll 100 men with treatment resistant prostate cancer and use advanced technology to capture and analyze cancer cells that are freely circulating in their bloodstreams. This trial will allow the researchers to look for early signs of treatment response or failure in individual cancer cells and examine the genetic and other molecular factors that indicate or lead to either a response or lack of response to chemotherapy. This is one of the few studies to utilize blood-based biomarkers in a prospective fashion. It is also a demonstration of cooperation between academic partners and the pharmaceutical industry—one that was facilitated by the Prostate Cancer Foundation.
- Prostate circulating tumor cells metastasize to bone via E-selectin expressed on endothelia cells.
This poster describes a molecular dance that prostate tumor cells exploit as they metastasize to bone. Understanding and characterizing the mechanisms that tumor cells use exit the bloodstream and to home to bone and set up shop should allow researchers to develop ways to interrupt the process and prevent circulating prostate cancer tumor cells from setting up cancerous shop in men’s bones. (Note: Dr. Tagawa’s name was added to the poster at presentation at AACR, but does not appear on the abstract link below.)
Read more about Dr. Tagawa and his work here.
These are but a few examples of the innovative work of PCF Young Investigators and how they are helping to accelerate discovery within PCF’s research enterprise with the end goal of ending suffering from prostate cancer and improving patient outcomes. PCF’s support of Young Investigators also ensures a robust pipeline of talent and ideas to keep the research process vibrant and successful. For more information on all PCF YIs, go to http://www.pcf.org/younginvestigators.