The treatment of cancer may soon get a shot in the arm as researchers come closer to understanding the link between the disease and the diversity of microbes, fungi and viruses in a person’s gut.

Recently, oncologists found that the variety and composition of what lives in the gastrointestinal tract affects how patients respond to cancer treatments. A key is a person’s gut microbiome, which could serve as a predictor to identify patient populations and potential therapeutic targets.

Hua Pan, PhD, MBA

A better understanding of this relationship could lead to new techniques for improving cancer outcomes and reducing the toxicity of anti-cancer treatments, according to researchers at the USF Health Heart Institute and the USF Initiative on Microbiomes project.

By far, knowledge is limited on how cancer treatments alter gut microbiome, and how dysbioisis – a microbial imbalance – caused by these treatments impair normal cardiovascular function, said Hua Pan, PhD, MBA, assistant professor of medicine at the Institute.

“We now have over 18 million cancer survivors, but many are facing the problem of cardiovascular complications. Cancer cells use newly generated blood vessels to support their growth, and anti-cancer treatment destroys the blood vessels for the cancer but also for the normal part of the body.’’         

Hua Pan, PhD, MBA, assistant professor at the USF Health Heart Institute

Pan wants to connect the dots. She’s focusing on the interplay among the microbiome, vessel damage, and heart failure after patients receive cancer treatment. This research is important, she said, because cardiovascular complications caused by the toxins in cancer treatment are a leading cause of death among cancer survivors. Moreover, cardiotoxicity is one of the reasons cancer patients don’t continue receiving treatment.

Armed with more knowledge about how the microbiome affects cardiovascular complications, researchers hope to identify high-risk patient populations for next-generation nanotherapy. Rather than a general treatment, these high-risk populations might receive more personalized treatment based on their microbiome.

Certain cancer therapies can increase the risk of damage to the heart and cardiovascular system.

“We hope to generate a product (from the microbiome) that could have a predictive value for cancer patients who are more susceptible to cardiovascular problems,’’ Pan said. “That would help us identity the right population for a certain therapy. It’s a personalized treatment.’’

Although many questions remain about the effect of microbiota on cancers and treatments, the Initiative on Microbiomes is bringing researchers closer to the right answers.

“It’s very promising, definitely,’’ she said. “And it one day could reduce health care costs, which today are almost 18% of the gross national product in the United States.’’

-Story by Kurt Loft

A Washington University-USF Health preclinical study finds that the novel nanoparticle delivers gene-level treatment to suppress KRAS-driven cancer without adverse effects

Despite advances in cancer survival, more than 90 percent of people with pancreatic cancer die within five years. Most patients with pancreatic tumors (and half of those with colorectal cancers) carry a mutation in the KRAS gene, which normally controls cell growth and death.

The KRAS oncogene was discovered more than 35 years ago and is considered one of the most desirable targets in cancer biology — particularly for cancers (like pancreatic) often diagnosed late and in desperate need of improved therapies to prolong survival. Yet KRAS has earned a reputation as being “undruggable” by researchers who continue searching for effective ways to inhibit the mutated form of RAS proteins driving the growth of deadly tumors.

Now a preclinical study led by Washington University School of Medicine in St. Louis, including co-investigators at the University of South Florida Health (USF Health) Morsani College of Medicine, Tampa, Fla., has demonstrated that specially designed peptide-based nanoparticles can suppress pancreatic cancer growth without the toxic side effects and therapeutic resistance seen in drug trials. The findings were published July 30 in Oncotarget.

The nontoxic, peptide-based p5RHH nanoparticles designed by USF Health researchers Samuel Wickline, MD, and Hua Pan, PhD, MBA, deliver an RNA molecule known as small interfering RNA, or siRNA (also known as silencing RNA). The molecules silence the chemical signal (message) telling the KRAS oncogene to make more mutated KRAS proteins that cause pancreatic cells to grow uncontrollably and largely resist existing cancer-killing drugs.

Confocal microscopy image shows fluorescent-tagged nanoparticles (pink) carrying siRNA diffusely taken up by mouse colorectal cancer cells.| Photo courtesy of Washington University School of Medicine in St. Louis

“We’ve developed a nanoparticle system that gets enough of the therapeutic molecule from the bloodstream to the tumor cell without (the molecule) being metabolized or excreted,” said coauthor Dr. Wickline, professor of cardiovascular sciences and director of the USF Health Heart Institute. “The nanoparticle is actively taken up by the targeted tumor cells and then the molecule escapes and does its job to prevent production of mutated KRAS proteins.”

“Approaches that precisely target tumors with various therapies are the future of cancer care. Nanoparticle delivery allows higher concentrations of drugs to reach their target while sparing normal tissues any side effects,” said senior author Ryan Fields, MD, professor of surgery and chief of surgical oncology at Washington University School of Medicine. “In pancreatic cancer, where breaking through the resistant tumor microenvironment is a current unmet need, this approach has the potential to improve therapeutics and patient outcomes.”

Compared to control cells, nanoparticle treatment of both pancreatic and colorectal cells was shown to deliver KRAS-specific siRNA, decrease KRAS RNA expression and lead to increased tumor cell death. Using a genetically engineered mouse model for spontaneously arising pancreatic cancer, the researchers also demonstrated that the intravenously administered nanoparticles could selectively target silencing RNA against the KRAS oncogene to ultimately slow KRAS-driven pancreatic cancer growth.  Their system effectively delivered this nanotherapy even in the “stroma-rich” environment of pancreatic tumors.

3D reconstruction of a single pancreatic cancer cell treated with siRNA nanoparticles. Confocal microscopy depicts accumulation of strong fluorescent silencing RNA signaling (pink) within the cell membrane (cyan) boundaries, but separate from lysosomes (yellow) that can degrade the nano-delivered molecules. | Photo courtesy of Washington University School of Medicine in St. Louis

Pancreatic cancer is so difficult to treat in part because fibrous tissue, or stroma, that surrounds the solid tumor “like the shell of a clam” is much denser than the stroma surrounding other more treatable tumors, Dr. Wickline explained. This protective stromal barrier can complicate nanoparticle-delivered treatment.

“Our p5RHH peptide nanoparticle is relatively small and it can squeeze in and out of tight spaces to get (treatment) safely into tumor-specific cells while staying out of normal tissue,” he said.  “It avoids adverse ‘off-target’ effects.”

Cancer is very efficient at evading treatments that target one, or even a few mutated genes or proteins, Dr. Wickline said. “The advantage of this nanoplatform carrying siRNA is that it’s easy to change out the target you want silenced, or add many more targets for simultaneous treatment in the same tumor cell.”

The nanoparticles formulated by Dr. Wickline and Dr. Pan have also shown promise for siRNA treatment in mouse models of atherosclerosis and arthritis.

The Oncotarget reported study was supported in part by grants from the National Cancer Institute.

Samuel Wickline, MD, and Hua Pan, PhD, researchers at the USF Health Heart Institute, designed the siRNA nanoparticle system tested in the study using tumor cells and a genetically engineered mouse model for pancreatic cancer. | Photo by Eric Younghans

USF Health’s Hua Pan, PhD, MBA, won first place for her moderated poster presentation titled “Anti-thrombin nanoparticles limit ischemia-reperfusion injury and no-reflow in myocardial infarction” on Sept. 2 at the annual European Society of Cardiology Congress in Paris. The Congress draws some 35,000 scientists from more than 100 countries over five days.

As part of the highly competitive presentation moderated by two chairpersons, Dr. Pan, a biomedical engineer and assistant professor of cardiovascular sciences at the USF Health Morsani College of Medicine, was required to present a 5-minute talk on the research poster in front of a group of audiences.  Her prize – free registration at next year’s Congress – was awarded for the poster session covering innovations in cardiac magnetic resonance Imaging.

USF Health Heart Institute’s Hua Pan, PhD, MBA

Dr. Pan and colleagues at the USF Health Heart Institute developed antithrombosis perfluorocarbon nanoparticles, which act as “smart Band-Aids” to find and stay only at the injured area in the heart to deliver treatment. These nanoparticles were evaluated in a rat model for heart attack and their treatment effect was visualized by MRI.  The study showed that the treatment limited further vascular damage from ischemia-reperfusion injury (IRI), a common complication following acute treatment of heart attacks.

Ironically, when blood flow is restored to the region of the heart injured by a blood clot that blocks the coronary artery, this blood reflow can expand injury to tissue surrounding the initial heart attack and lead to congestive heart failure. In explaining IRI, Dr. Pan compares an obstructed blood vessel to a clogged water pipe, already weakened by prior damage, which may leak once the pipe is unclogged and water (blood) flows freely again.

“The antithrombin nanoparticles we developed acted locally to preserve the blood vessels (pipes) in the heart, so that the restored blood reached areas where the treatment was needed, without leaking into areas where it could cause more harm,” Dr. Pan said.  The precision nanoparticle treatment calmed unnecessary inflammation as well as inhibiting the thrombin from forming more blood clots leading to blood vessel obstructions in the heart, she added. It did so without causing the bleeding risk associated with existing anticoagulant drugs.

Because the antithrombin nanoparticles “do not prolong bleeding times or coagulation parameters beyond approximately 30 to 60 minutes after injection, yet maintain prolonged surveillance against activated thrombin locally in the injured area, they represent a potentially useful therapy for cardiac IRI,” Dr. Pan and her poster co-authors concluded.

USF Health Heart Institute scientists developed nanoparticles deployed to suppress inflammation in the bowels of anemic infant mice, preventing transfusion-associated intestinal injury

Babies born prematurely who are severely anemic can develop necrotizing enterocolitis, or NEC, within 48 hours after receiving a red blood cell transfusion.

Physicians have long suspected that red blood cell transfusions given to premature infants with anemia may put them in danger of developing necrotizing enterocolitis, or NEC, a potentially lethal inflammatory disease of the intestines. However, solid evidence for the connection has been difficult to obtain in part because of the lack of a practical animal model able to accurately represent what physically occurs when a baby gets NEC.

Now, a research team led by Johns Hopkins Medicine, including USF Health Morsani College of Medicine collaborators, describes the development of a new model — using infant mice, or pups, that are first made anemic and then given blood transfusions from neonates of a different mouse strain. The method, the researchers say, mimics what happens when blood transfusions are given to human babies from a non-related donor.

“We needed a working live mouse model in order to learn if a blood transfusion alone leads to NEC or does it only happen if the transfusion is given when anemia is present,” says Akhil Maheshwari, MD, professor of pediatrics at the Johns Hopkins University School of Medicine, director of neonatology at Johns Hopkins Children’s Center, and senior author of the research paper.

A description of the mouse model, along with significant findings and potential benefits from its first uses, is published in a new paper in the journal Nature Communications.

Maheshwari, a professor of pediatrics at USF Health before joining Johns Hopkins Medicine (Baltimore) in 2018, conducted much of the research published in the paper while he was at the USF Health and Tampa General Hospital. Nanoparticles designed by USF Health coauthors Samuel Wickline, MD, and Hua Pan, PhD, were employed to test whether immune cells (macrophages) in the intestines of the anemic infant mice must undergo inflammatory activation to cause bowel injury.

More common in severely anemic preemies after transfusion

Seen in approximately 10% to 12% of infants weighing less than 3.5 pounds at birth, NEC is a rapidly progressing gastrointestinal emergency in which bacteria invade the wall of the colon, causing inflammation that can ultimately destroy healthy tissue at the site. If enough cells are necrotized (killed) that a hole results in the intestinal wall, fecal material can enter the bloodstream and cause life-threatening sepsis.

Since 2004, Maheshwari says, research studies have repeatedly shown that babies born prematurely who are severely anemic — those with a proportion of red blood cells to total blood volume between 20% and 24% at birth — can develop NEC within 48 hours after receiving a red blood cell transfusion. By comparison, the American Academy of Pediatrics says that babies delivered at term normally have red blood cell volumes between 42% and 65%, dropping to between 31% and 41% at age 1.

In search of a useful and practical mouse model, Maheshwari and his colleagues had to overcome a size problem. “Newborn mouse pups are about the size of a quarter and weigh less than an ounce, so it’s extremely difficult to remove enough blood from them for laboratories to analyze,” Maheshwari says.

A new working mouse model was used to investigate whether blood transfusions alone leads to NEC, or if the potentially deadly inflammatory disease only occurs only when tranfusions are administered in the presence of anemia.

To get past that obstacle, a private medical diagnostic equipment company donated the use of its advanced blood analysis system that only requires a 5 microliter (5 millionths of a liter) sample instead of the 50 microliters — 60% of a mouse pup’s total blood supply — that most testing labs require.

Next, the researchers designed a procedure to induce severe anemia in the pups by removing about half of their blood volume every other day for 10 days after birth. This dropped their red blood cell counts to levels approximating those in severely anemic newborn babies.

Seven days after birth, the researchers introduced bacteria that had been isolated and cultured from a premature infant with NEC. Finally, red blood cell transfusions were given on the 11th day after birth.

Over the next 48 hours, the researchers looked for development of NEC-like symptoms in their experimental group and three other sets of mouse pups: (1) a control group without any intervention, (2) a group without anemia that received transfusions and (3) a group with anemia but not transfused.

“Only the severely anemic pups who received blood transfusions showed intestinal damage that resembled human NEC with necrosis, inflammation and separation of the tissues supporting the lining of the colon,” Maheshwari says. “The next step was to see if we could find a mechanism for why this occurred.”

A “double whammy” on the intestinal wall

Examining the blood of the pups with NEC-like conditions after they were transfused, the researchers discovered that it contained three components not seen in the blood of the other test mice: (1) a large number of macrophages, the immune cells that engulf and digest cellular debris, bacteria and viruses, (2) freely circulating hemoglobin, the iron-based molecules that normally carry oxygen throughout the body when attached to red blood cells, and (3) elevated levels of inflammation-inducing proteins, indicating that the macrophages had been activated even without a biological threat to the intestine.

The researchers also observed that levels of haptoglobin, a protein that removes free hemoglobin from the blood, were extremely low.

“These findings suggest that anemia reduces the amount of haptoglobin in the neonate, preventing the free hemoglobin that comes in via transfusion from being properly removed as it normally would,” Maheshwari says.

What apparently happens, he says, is that free hemoglobin attaches to a protein receptor on the intestinal wall that is the same site where bacterial poisons bind. As a result, the immune system mistakenly believes the intestine is being attacked and activates the macrophages.

Once those immune cells go to work, Maheshwari explains, they trigger release of the inflammatory proteins seen in the blood of the anemic, transfused mice. “That event starts a double whammy on the intestinal wall,” he says. “First, the macrophage proteins inflame and weaken the tissues, making them vulnerable, and then, bacteria move in and produce endotoxins that kill the individual cells.”

Johns Hopkins Medicine senior author Akil Maheshwari, MD, says he hopes the findings from the current study can be used to develop blood biomarkers that could indicate which human newborns are most at risk of developing NEC.

With evidence for a probable mechanism to explain the connection between anemia and transfusion in the development of NEC, the researchers next sought to confirm it by seeing if they could block two of its stages, and perhaps, advance the search for potential therapies.

“In one trial, we gave haptoglobin to our model anemic mice before transfusing them and blocked macrophage activation, so they did not develop NEC-like symptoms,” Maheshwari says.

Controlling a master regulator of inflammation in NEC

In another test, nanoparticles that Samuel Wickline, MD, and his colleagues at the University of South Florida  Health developed were used to deliver a genetic interruption — an RNA molecule known as a small interfering RNA, or siRNA — that blocks the chemical signal telling macrophages to start producing inflammatory proteins. The nanoparticles were tagged with a fluorescent dye to track their movement and included a non-toxic compound derived from honeybee venom.

Maheshwari says the macrophages in the blood of anemic mouse pups engulfed the nanoparticles and enclosed them within vacuoles. The bee venom derivative, he explains, broke open the vacuoles so that the siRNA could be released inside the macrophages.

The genetic signal blocker worked well, Wickline says, protecting the anemic mouse pups from intestinal inflammation after red blood cell transfusions.

“Because we showed that the inhibitory nanoparticles with siRNAs were able to control a master regulator of inflammation in NEC, perhaps this technology can one day be applied to not only treat or prevent NEC, but other diseases where inflammation plays a key role such as arthritis and atherosclerosis,” he says. “We had previous shown in preclinical studies that while these peptide siRNA nanoparticles can suppress harmful inflammation, they do not affect levels of an inflammatory signaling molecule (NF-kB) important in protecting normal tissues. That sets the stage for clinical testing in the near future.”

Maheshwari says he hopes the new mouse model and the findings from the current study can be used to develop blood biomarkers that could indicate which human newborns are most at risk of developing NEC.

Research paper coauthors Samuel Wickline, MD, and Hua Pan, of the USF Health Morsani College of Medicine, developed the nanoparticles used in the study.

Funding for this investigation came from National Institutes of Health (NIH) awards HL124078 and HL133022, and American Heart Association award 14GRNT20480307, given to Maheshwari; and NIH awards HL073646, DK102691 and AR067491, given to Wickline. Sysmex America donated the use of its automated veterinary hematology analyzer that made possible the mouse model developed in this study.

Collaborating on the study were researchers from the Johns Hopkins University School of Medicine, the Morsani College of Medicine at the University of South Florida, the Yale School of Medicine and the University of Alabama at Birmingham. Along with Maheshwari and Wickline, the team members included lead author Mohan Kumar Krishnan, Kopperuncholan Namachivayam, Tanjing Song, Byeong Jake Cha, Andrea Slate, Jeanne Hendrickson, Hua Pan, Joo-Yeun Oh, Rakesh Patel, Ling He and Benjamin Torres.

-This story is an edited version of a news release by Johns Hopkins Medicine. 

The peptide-siRNA nanoparticle technology applied in the preclinical study was developed by USF Health Heart Institute researchers

Advanced ovarian and uterine cancers are deadly diseases. Ovarian cancers, in particular, present with vague symptoms common to other diseases, and often are not diagnosed until a late stage when cancer has spread throughout the abdomen.  More options are needed to effectively treat these metastasized gynecological cancers and improve patient survival rates.

A preclinical study published recently in Scientific Reports demonstrates that nanoparticle-delivered small interfering RNA (siRNA) targeting production of the protein AXL (AXL siRNA) inhibits metastasis of ovarian and uterine cancer cells.  The study was conducted by researchers at Washington University School of Medicine, St. Louis, Mo., and the USF Health Heart Institute, University of South Florida Morsani College of Medicine, Tampa, Fla.

3D illustration of ovarian cancer

The research team used a new nanoparticle system developed by USF Health co-investigators Samuel Wickline, MD, and Hua Pan, MBA, PhD, to test the experimental nanotherapy in human uterine and ovarian tumor cells and in immunodeficient mice implanted with these cancer cells.

“We’ve figured how to package in a simple peptide all the critical steps needed to efficiently get this particular small interfering RNA (also known as silencing RNA) into tumor cells and then release the siRNA so it can do its job,” said Dr. Wickline, a professor of cardiovascular sciences who direct the USF Health Heart Institute. “The nanoparticle basically hijacks the tumor cells’ biological machinery to get the siRNA where it needs to go – without being destroyed along the way, or creating harmful side effects.”

The nanoparticle combines two components in one delivery package 100 times smaller than a red blood cell: AXL siRNA and the peptide p5RHH.  AXL siRNA is designed to target and silence the expression of AXL, a key molecule that drives uterine and ovarian cancers. The p5RHH nanoparticles are derived from a major substance of bee venom called melittin, detoxified and selectively modified to facilitate timely escape of AXL siRNA from the nanostructure once the silencing RNA is delivered inside the targeted tumor cells.

Among the findings of the Washington University-USF Health study:

• In cell culture, treatment with p5RHH-siAXL nanoparticles decreased the ability of uterine and ovarian cancer cells to migrate and invade neighboring normal tissues.
• Mice with established uterine and ovarian tumors were intravenously and abdominally (intraperitoneally) injected with nanoparticles containing p5RHH and fluorescent control siRNA. The peptide nanoparticles localized to and released their contents into both tumor cell types regardless of the injection route, but fluorescent imaging showed that intraperitoneal administration was more effective than IV administration.
• In the mouse models, p5RHH-siALX treatment significantly reduced metastasis of both uterine and ovarian cancer without toxic effects.

USF Health Heart Institute Director Samuel Wickline, MD, and biomedical engineer Hua Pan, PhD, build nanoparticles to safely and efficiently deliver drugs or other therapeutic agents to specific cell types.

Overall, the study demonstrates this nanoparticle approach shows promise for treating patients with ovarian or uterine cancers, the authors conclude.

Challenges in translating preclinical successes into patient care remain, but Dr. Wickline believes nanoparticle-mediated delivery of siRNA has applications beyond just suppressing one target (AXL) implicated in other cancers in addition to uterine and ovarian.

The power of harnessing tiny nanotechnology for gene therapies lies in its flexibility, he said.

“As we identify new disease-modifying targets, it offers the potential to attack multiple different targets at the same time.  So, one nanoparticle could deliver a whole host of genetic materials – a combination of RNA interference drugs, or other types of synthetic RNA or DNA-based drugs —  to hit any specific cell types where treatment is needed.”

Michael Fradley, MD, had finished medical school. He’d completed training in internal medicine and cardiology.   He decided to pursue further training in electrophysiology, and began observing a substantial number of cancer patients were experiencing abnormal heart rhythms.   Then, in the midst of his fellowship, the unthinkable happened.  He received his own cancer diagnosis – melanoma.

“I had to undergo certain procedures and treatments but fortunately now I’m fine,” said Dr. Fradley, associate professor of medicine at the USF Health Morsani College of Medicine.  “As a result of this experience, I had this very new perspective on my life and my career. I had been personally affected by cancer … and I have this passion for cardiology. Wouldn’t it be an amazing opportunity to try to bring the two together?”

USF Health cardiologist Michael Fradley, MD, speaks to a patient at the Cardio-Oncology Clinic at Moffitt Cancer Center.

While Dr. Fradley was finishing his electrophysiology fellowship, Roohi Ismail-Khan, MD, a medical oncologist at Moffitt Cancer Center, was noticing a worrying trend — many of her breast cancer patients experienced cardiac issues during and after treatment. “We were getting much better at treating cancer,” she said, but “why put patients through something that’s going to help them survive the cancer and then have [cardiac] issues to deal with later on?” So, in late 2014, about a year after Dr. Fradley joined the cardiology team at USF Health, the pair began a Cardio-Oncology Program jointly developed by USF Health and Moffitt. “It was all just a perfect fit,” Dr. Fradley said.

Integrating research into cardio-oncology care

Cardio-oncology is an emerging field — one in which there are still many questions left to answer. Dr. Fradley and Dr. Ismail-Kahn didn’t just want to treat patients; they wanted to research how to do it better. They enlisted the help of biomedical engineer Hua Pan, PhD, MBA, an assistant professor of cardiovascular sciences and member of the USF Health Heart Institute. Dr. Pan conducts basic and translational research on the molecular mechanisms through which cancer treatments damage the heart. This includes investigating genetic signals that may help predict which patients receiving new drugs to boost the body’s immune system response against certain cancers are likely to develop cardiovascular complications.

Biomedical engineer Hua Pan, PhD, a member of the USF Health Heart Institute, works with Dr. Fradley and collaborators at Moffitt Cancer Center to incorporate basic science and translational research into the joint Cardio-Oncology Program.

The cardiologist, oncologist and basic scientist came together to form a powerful academic research and training program. “It’s one of the first [cardio-oncology programs] in this nation to incorporate basic science and the translational component into a cardio-oncology program,” Dr. Pan said. “It connected the dots. This is very unique.”

There was a time when a cancer diagnosis was almost equivalent to a death sentence. Nowadays, nearly 70% of people diagnosed with cancer will survive, thanks to the advent of treatments like chemotherapy, radiation therapy, and immunotherapy, according to the National Cancer Institute. But those life-saving therapies have come at a cost. Up to 30% of cancer patients develop cardiovascular complications. The issue is so common that it’s become the leading cause of death in cancer survivors. Those therapies, which so effectively attack cancer cells, can also damage the heart and increase the risk of heart disease in the future. And if a patient is already at risk of heart disease due to obesity, diabetes, or genetics, that risk is amplified by cancer treatment.

A collaboration that optimizes treatment

That’s something Dr. Ismail-Kahn had to consider when treating patients. For patients with clear risk factors for heart disease, she might choose a less aggressive — and potentially less effective — treatment plan to avoid cardiac complications.

Now, when a patient comes to see Dr. Ismail-Kahn for cancer treatment, she sets the patient up with an appointment with Dr. Fradley as well. Dr. Ismail-Kahn determines the ideal treatment for the patient’s cancer. She’ll send that information to Dr. Fradley, who after reviewing the patient’s cardiac history and conducting various tests on the patient’s heart and blood, will develop a plan to monitor and prevent cardiovascular complications throughout treatment. That plan may require guiding the patient through preventive measures like changes in diet and exercise or starting the patient on cardiac medications. It will also include regular cardiac checkups with Dr. Fradley so he can identify any cardiac effects before they become severe and offer an intervention or suggest a temporary break from cancer treatment if needed.

Moffitt Cancer Center oncologist Roohi Ismail-Khan, MD

“Let’s just say I have an 80-year-old patient with history of heart disease and she needs certain chemotherapy and certain targeted therapy to help with her cancer,” Dr. Ismail-Kahn said. Before working with a cardio-oncologist, she might have chosen a less effective treatment plan in order to prevent heart disease. Now, she says she’s “braver in treating patients.” Working with a cardio-oncologist who understands how cancer drugs interact with the heart, can watch the heart closely, and knows what interventions can help, gives her confidence that any cardiovascular risks will be managed appropriately so that she can give the right treatment for each patient.

One of the nation’s first cardio-oncology fellowships

But there aren’t enough cardio-oncologists for all programs to offer such care. As such, Dr. Fradley developed one of the first cardio-oncology fellowship programs in the United States, focusing on training a new generation of cardiologists to specialize in this field. ‘It’s important for trainees to get dedicated exposure to the complexities of this patient population,” Dr. Fradley explained. “This is an excellent opportunity to disseminate knowledge to other institutions and organizations. And these individuals will become the future leaders of the specialty.”

Moving the field forward will take more than training new specialists. That’s why the program is set up to conduct multidisciplinary research while it offers its multidisciplinary treatment. The physicians treating patients every day see first-hand which questions need to be answered to improve care. Not only do they design studies to test clinical interventions, but they pass their questions along to Dr. Pan through a special communication channel designed by Dr. Fradley to facilitate conversations between the extremely busy team members. Dr. Pan can use their observations to guide her studies looking at what patients are experiencing on a molecular level. This understanding can then be used to develop better, more precise treatments.

“A combination of both clinical investigation and translational research is necessary to advance the field,” Dr. Fradley said.

Cancer survivor Abby Jones with her husband Ross on a recent vacation in Colorado. Jones, one of the first patients in the Cardio-Oncology Program jointly developed by USF Health and Moffitt Cancer Center, credits the program with playing a “huge part” in helping restore her health.

Heart healthy and cancer free

The future of cardio-oncology is exciting, but the program is already making a huge difference for patients in Florida, like Abby Jones of Ocala.  Jones was one of the very first patients to participate in the program for cancers of her lung and kidney (removed completely by surgery) and breast cancer. She was young and otherwise healthy, so Dr. Ismail-Khan decided to treat Jones’ bilateral breast cancer with the most aggressive therapy available.  During chemotherapy and targeted therapy with the drug trastuzumab (a combination with a high likelihood of cure, but that can have toxic effects on the heart), Jones received routine echocardiograms to monitor her cardiac function.  When one of echocardiograms revealed that her heart wasn’t pumping effectively, Dr. Ismail-Khan immediately referred Jones to Dr. Fradley in the Cardio-Oncology Clinic.

Dr. Fradley recommended a 7-week break from the chemotherapy, during which Jones took low-dose blood pressure medications. Soon, she was able to safely continue her chemotherapy. Today, she is cancer-free. (In fall 2016, a different type of breast cancer was detected early; Jones underwent a lumpectomy, her heart was closely monitored during another potentially cardiotoxic chemotherapy regimen, and the treatment succeeded without cardiac complications.)

Jones continues annual appointments with Dr. Fradley to ensure her heart remains healthy, and follows up with Dr. Ismail-Khan to make sure she remains cancer-free.

“I’m two years clean from the most recent diagnosis and celebrating life. The Cardio-Oncology team played a huge part in helping me get back to myself,” she said. “We welcomed newborn twins into our home as foster children earlier this year with a goal of adoption on the horizon.  And last month, I got to drop my oldest off at his first day of kindergarten… it was so fun to watch!”

Jones with Dr. Fradley and Dr. Ismail-Khan at a luncheon in February 2016, marking the first year of the newly established Cardio-Oncology Program.

###

Moffitt Cancer Center and USF Health (with Drs. Fradley and Ismail-Khan as co-chairs) will host the fourth Cardio-Oncology Summit, Sept. 27 and 28, at the Hilton Tampa Downtown, alongside the International Cardio-Oncology Society, the Canadian Cardiac Oncology Network and the British Cardio-Oncology Society.  This is the summit’s first time in Tampa; previous conferences have been held in London, Vancouver and Nashville. More than 320 participants from 23 countries are expected to attend the summit, which models a leading-edge interdisciplinary approach to preventive and targeted medicine in cardio-oncology. Read more.

-Story by Emma Yasinski

The founding director of the USF Health Heart Institute has a passion for innovation, translational medicine and entrepreneurship.

Samuel A. Wickline, MD, has parlayed his expertise in harnessing nanotechnology for molecular imaging and targeted treatments into an impressive $1-million portfolio of National Institutes of Health awards, multiple patents and four start-up biotechnology companies.

“We’ve developed nanostructures that can carry drugs or exist as therapeutic agents themselves against various types of inflammatory diseases, including, cancer, cardiovascular disease, arthritis and even infectious diseases like HIV,” said Dr. Wickline, who arrived at USF Health last month from the Washington University School of Medicine in St. Louis.

Dr. Wickline: “Innovation is not just about having a new idea, it’s about having a useful idea.”

 Dr. Wickline comments on how being a physician adds perspective to the science he conducts.

At Washington University, Dr. Wickline, a cardiologist, most recently was J. Russell Hornsby Professor in Biomedical Sciences and a professor of medicine with additional appointments in biomedical engineering, physics, and cell biology and physiology.

“I like the challenge of building things,” he said.

In St. Louis, he built a 29-year career as an accomplished physician-scientist keenly interested in translating basic science discoveries into practical applications to benefit patients. He served as chief of cardiology at Jewish Hospital, developed one of the first cardiac MRI training and research programs in the country, helped establish Washington University’s first graduate program in biomedical engineering, and led a university consortium that works with academic and industry partners to develop medical applications for nanotechnology.

At USF, there will be no shortage of challenging opportunities to build.

Building the USF Health Heart Institute

A major part of Dr. Wickline’s new job is helping to design, build and equip the Heart Institute. Most importantly, he will staff the state-of-the-art facility with a critical interdisciplinary mix of top biomedical scientists (including immunologists, molecular biologists, cell physiologists and genomics experts), who investigate the root causes of heart and vascular disease with the aim of finding new ways to detect, treat and prevent them. The Heart Institute will be co-located with new Morsani College of Medicine in downtown Tampa; construction on the combined facility is expected to begin later this year.

“I have been impressed by the energy and commitment here at the University of South Florida to invest substantial resources in a heart institute,” Dr. Wickline said. “I believe we have a lot to offer in terms of bench-to-bedside research that could solve some of the major cardiovascular problems” like atherosclerosis or heart failure.

“We want to put together a program that supplies the appropriate core facilities to attract the best and brightest researchers to this cardiovascular institute.”

Cardiovascular disease is the leading cause of death in the United States and worldwide, so exploring potential new treatment options is critical. One of the Heart Institute’s driving themes will be advancing concepts and findings that prove promising in the laboratory into projects commercialized for clinical use, Dr. Wickline said.

“Our goal is to make a difference in the lives of patients,” he said. “Innovation is not just about having a new idea, it’s about having a useful idea.”

Dr. Wickline also serves as associate dean for cardiovascular research and a professor of cardiovascular sciences at the Morsani College of Medicine. He holds the Tampa General Endowed Chair for Cardiovascular Research created last year with a gift from USF’s primary teaching hospital.

With Washington University colleague Hua Pan, PhD, a biomedical engineer and expert in molecular biology, Dr. Wickline is re-building his group at USF. Dr. Pan was recently recruited to USF as an assistant professor of medicine to continue her collaborations with Dr. Wickline.

 An example of Dr. Wickline’s group using nanotechnology to help combat atherosclerosis.

Dr. Wickline’s lab focuses on building nanoparticles to deliver drugs or other therapeutic agents to specific cell types, or targets.

Designing nanoparticles to “kill the messenger”

Dr. Wickline’s lab focuses on building nanoparticles – shaped like spheres or plates, but 10 to 50 times smaller than a red blood cell – to deliver drugs or other therapeutic agents through the bloodstream to specific cell types, or targets. These tiny carrier systems can effectively deliver a sizeable dosage directly to a targeted tissue, yet only require small amounts of the treatment in the circulation to reduce the risk of harmful side effects.

Some types of nanoparticles can carry image-enhancing agents that allow researchers to quantify where the illuminated particles travel, serving as beacons to specific molecules of interest, and enabling one to determine whether a therapeutic agent has penetrated its targeted site, Dr. Wickline said.

Dr. Wickline also is known for designing nanoparticles derived from a component of bee venom called melittin. While bee venom itself is toxic, Dr. Wickline’s laboratory has detoxified the molecule and modified its structure to produce a formula that allows the nanoparticles to carry small interfering (siRNA), also known as “silencing RNA,” or other types of synthetic DNA or RNA strand.

Among other functions, siRNA can be used to inhibit the genes that lead to the production of toxic proteins. Many in the nanotechnology research and development community are working to make siRNA treatment feasible as what Dr. Wickline calls “a message killer,” but the challenges have been daunting.

“The big challenge in the field of siRNA, and many companies have failed at this, is how to get the nanostructure to the cells so that the siRNA can do what it’s supposed – hit its target and kill the messenger — without being destroyed along the way, or having harmful side effects,” Dr. Wickline said. “We figured out how to engineer into a simple peptide all of the complex functionality that allows that to happen.”

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 Dr. Wickline comments on the underlying similarities between cardiovascular disease and cancer.

Different targets, same delivery vehicle

In a recent series of experiments in mice, Dr. Wickline and colleagues have shown that silencing RNA messages delivered by nanoparticle to a specific type of immune cell known as a macrophage – a “big eater” of fat – actually shrinks plaques that accumulate inside the walls of the arteries during atherosclerosis, one of the main causes of cardiovascular disease. The build-up of atherosclerotic plaques with fat-laden macrophages narrows, weakens and hardens arteries, eventually reducing the amount of oxygen-rich blood delivered to vital organs.

This type of plaque-inhibiting nanotherapy could be useful in aggressive forms of atherosclerosis where patients have intractable chest pain or after an acute heart attack or stroke to prevent a secondary cardiac event, Dr. Wickline said.

In another study, Washington University School of Medicine researchers investigated the potential of the siRNA nanoparticle designed by co-investigators Dr. Pan and Dr. Wickline in treating the inflammation that may lead to osteoarthritis, a degenerative joint disease that is a major cause of disability in the aging population. The nanoparticles — injected directly into injured joints in mice to suppress the activity of the molecule NF-κB — reduced local inflammation immediately following injury and reduced the destruction of cartilage. The findings were reported September 2016 in the Proceedings of the National Academy of Sciences.

Previously, Dr. Wickline said, the Washington University group had shown that nanoparticles delivered through the bloodstream inhibited inflammation in a mouse model of rheumatoid arthritis. And, another laboratory at the University of Kentucky is studying whether locally injected siRNA nanoparticles can quell the bacterial inflammation that can lead to a serious gum disease known as periodontitis. Other collaborating labs are using these nanoparticles in pancreatic, colon, and ovarian cancers with good effects.

“The specific targets in these cases may be different, but the nice thing about this kind of delivery system for RNA interference is that the delivery agent itself, the nanostructures, are the same,” Dr. Wickline said. “All we have to do is change out a little bit of the genetic material that targets the messages and we’re set up to go after another disease. So it’s completely modular and nontoxic.”

The St. Louis-based biotechnology company Trasir Therapeutics is developing these peptide-based nanocarriers for silencing RNA to treat diseases with multiple mechanisms of inflammation. Dr. Wickline co-founded the company in 2014 and continues to serve as its chief scientific officer.

Dr. Wickline with colleague Hua Pan, PhD, a biomedical engineer with expertise in molecular biology.

 Inhibiting chronic inflammation without getting rid of beneficial immune responses.

Calming the destructive cycle of inflammation

Dr. Wickline’s work is supported by several NIH RO1 grants, including one from the National Heart, Lung and Blood Institute to develop and test nanotherapies seeking to interrupt inflammatory signaling molecules and reduce the likelihood of thrombosis in acute cardiovascular syndromes.

In essence, Dr. Wickline said, he is interested in suppressing chronic inflammation, without disrupting the beneficial functions of surveillance by which the immune system recognizes and destroys invading pathogens or potential cancer cells.

“If you can inhibit the ongoing inflammation associated with (inappropriate) immune system response, you inhibit the positive feedback cycle of more inflammation, more plaques, more damage and more danger,” he said. “If you can cool off inflammation by using a message killer that says (to macrophages) ‘don’t come here, don’t eat fat, don’t make a blood clot’ – that’s what we think could be a game changer.”

Another NIH grant has funded collaborative work to develop an image-based nanoparticle that detects where in a compromised blood vessel too much blood clotting (hypercoagulation) occurs, and delivers potent anti-clotting agent only to that site. Formation of abnormal blood clots can trigger a heart attack when a clot blocks an artery that leads to heart muscle, or a stroke when a clot obstructs an artery supplying blood to the brain.

Because this site-specific nanotherapy targets only areas of active clotting, it may provide a safer, more effective approach against cardiac conditions like atrial fibrillation and acute heart attack than existing anticoagulant drugs such as warfarin and newer blood thinners like Xarelto® (rivaroxoban) or Eliquis® (apixiban), all which work systemically and come with raised risk for serious bleeding, Dr. Wickline said.

In a study published last year in the journal Arteriosclerosis, Thrombosis, and Vascular Biology, Dr. Wickline and colleagues found that nanoparticles delivering a potent inhibitor of thrombin, a coagulant protein in blood that plays a role in inflammation, not only reduced clotting risk but also rapidly healed blood vessel endothelial barriers damaged during plaque growth.

The preclinical work showed the experimental treatment “is actually an anti-atherosclerotic drug as well as an anti-clotting drug, so there are many potential applications,” Dr. Wickline said.

Dr. Wickline received his MD degree from the University of Hawaii School of Medicine. He completed a residency in internal medicine, followed by clinical and research fellowships in cardiology at Barnes Hospital and Washington University, where he joined the medical school faculty in 1987.

He has authored more than 300 peer-reviewed papers and holds numerous U.S. patents. Dr. Wickline is a fellow of the American College of Cardiology and the American Heart Association, and a 2014 recipient of the Washington University Chancellor’s Award for Innovation and Entrepreneurship.

– Photos by Sandra C. Roa and Eric Younghans