--This post was written by freelance writer Becky Ham.

A compound made from the tree’s bark shows promise against tumors spurred by the leptin hormone.

Southern magnolia

Southern magnolia

Stand under the glossy green canopy of a southern magnolia in full bloom, and you’ll be dazzled by this queen tree’s show of hundreds of highly perfumed ivory blossoms, each the size of a teacup. It’s a stunning sight, but for centuries, Magnolia grandiflora has been known for more than its pretty face. The tree contains a pharmacopeia of sorts, yielding chemical compounds that have been used to treat everything from anxiety to heart attack.

Dipali Sharma, M.S., Ph.D., an associate professor of oncology at the Sidney Kimmel Comprehensive Cancer Center, thinks it may be time to add some breast cancers to this list of ailments. With her team at Johns Hopkins, Sharma is testing a magnolia compound called honokiol that seems to slow the growth of breast cancers fueled by an excess of leptin, a hormone closely connected with obesity.

Dipali and her colleagues have turned to honokiol after many years of studying the complicated role that leptin plays in breast cancer—and the role of obesity as a risk factor in many cancers. The well-known Million Woman study conducted through the University of Oxford suggested that about half the cancers in postmenopausal women in the United Kingdom can be attributed to obesity. Other studies have found that women at the highest body-mass index (BMI) levels have double the death rate from breast cancer, compared to those in the lowest BMI tier.

With nearly two-thirds of U.S. adults overweight or obese, according to U.S. Centers for Disease Control and Prevention, it’s a cancer risk factor that is poised to become “a very significant medical problem,” Sharma says. “Developing a preventive and therapeutic strategy for cancer in the obese state is extremely important.”

A Hormone’s Hyperactive Signals

Dipali Sharma

Dipali Sharma

Leptin is sometimes called the “starvation hormone,” although its role in the body is much more complicated. It is made by fat cells, and helps to regulate the body’s energy stores by suppressing hunger. People who are obese make more leptin because they have a higher percentage of body fat, but their bodies appear to be resistant to this hunger-inhibiting signal.

Unfortunately, the abnormal increased flow of leptin can trigger a variety of other changes in the body. Sharma and others have shown that leptin and its latch-like receptors on the surfaces of cells are overabundant in breast cancer cells, compared to normal breast cells. Their studies demonstrate that hyperactive leptin signaling by these cells causes the cancer cells to multiply and invade tissue, and spurs the growth of the blood vessels that feed tumors.

“We learned that leptin-induced tumors quickly learn to evade all the usual biological checkpoints that have been put in place to keep the tumors from growing and spreading fast,” says Sharma. Leptin helps the tumor cells make a critical change in their shape and mobility, she explains, “and after achieving this state, a tumor cell becomes poised to migrate and invade and transition from a primary, non-invasive tumor to an invasive tumor.”

The Johns Hopkins scientists realized that their results could help explain why advanced grade and stage cancers, including those that spread to the lymph nodes, are more prevalent in obese women with invasive breast cancer. So they set out to find a way to quiet leptin’s hyperactive signaling in these tumors.

The Magnolia Medicine Cabinet

Magnolia’s medical record is a long one, especially in places like China, Japan and the Korean peninsula. Records from China show that magnolia bark, called houpu, was used as early as 100 A.D. to treat digestion problems and breathing ailments such as asthma. The bark, cones and leaves from a variety of Magnolia species are taken in their whole form, as extracts or powders, or most often brewed into a herbal tea. In traditional Asian medicine, magnolia is prescribed as an anti-inflammatory drug, an anti-anxiety medicine, a blood thinner, and yes—an anticancer agent.

The chemical compound called honokiol, extracted from magnolia seed cones, appears to be one of a handful of biologically active ingredients in the magnolia plant. Researchers have tested honokiol in cells grown in the lab and in animals, and confirmed that the compound does have an array of medicinal properties. In the 1990s, the Emory University lab of cancer specialist Jack Arbiser developed new ways to purify the compound, leading to a flurry of studies in his lab testing honokiol’s anticancer properties against lymphocytic leukemia and myeloma, melanoma, breast and prostate cancers.

When Sharma and her colleagues began the search for a biologically active compound that would have anticancer activity and could shut down the leptin signaling network, honokiol leapt to the top of their list. It’s a small molecule, which makes it easier for the body’s cells to interact with and absorb. It doesn’t appear to be toxic except in very high doses, and it isn’t part of the hormone family that includes estrogen. This last point is important, says Sharma, because it means honokiol could “be used to treat estrogen-receptor (ER) positive as well as estrogen-receptor negative breast cancers.”

How Honokiol Works

In two studies (here and here) published last year in the journal Oncotarget, Sharma and her colleagues put honokiol under renewed scrutiny, first examining the effects of the compound on breast cancer cells grown in the lab. They discovered that honokiol can block the transformation and activation of some of the key molecules within leptin’s signaling network in these cells—most notably a signaling pathway that includes some well-known cancer-related proteins.

The researchers uncovered an especially intriguing role for a microRNA regulator called miR-34a. MicroRNAs are tiny snippets of genetic material that help to regulate how certain protein-coding genes are turned on and off. In a handful of other studies of miR-34a, scientists have identified the microRNA as an important tumor suppressor that is weakened in aggressive breast tumors. Now, for the first time the Johns Hopkins research team has shown that honokiol helps to keep miR-34a active and able to suppress some of the other cancer-linked proteins in the leptin network.

Sharma and her colleagues then fed some mice a high fat diet and watched their leptin levels rise, compared to those in mice on a normal diet. Breast tumors grown in the obese, hyper-leptin mice had low levels of the protective miR-34a, they soon discovered, but these levels rose when the mice were fed doses of honokiol. Over four weeks of treatment, these tumors grew to be significantly smaller in obese mice treated with honokiol, to about the half the size of the tumors in untreated obese mice.

The link between obesity, leptin and breast cancer has been strengthened by these and other studies. But Sharma says the findings haven’t yet changed how breast cancer patients are diagnosed or treated. “Currently, clinicians do not distinguish between leptin-induced or non-induced breast cancers,” she explains. “It’s not the usual clinical practice to check a patient for leptin or leptin receptor levels.”

She thinks the data collected by her lab and others will alter this practice in the future, especially since leptin signaling could affect how well standard breast cancer therapies work. Some studies suggest, for instance, that breast cancer cells that have exposed to high levels of leptin over several years might be less sensitive to treatments like tamoxifen.

The next steps would be to begin a clinical trial of honokiol in breast cancer patients who are obese, “and then move toward tests of all patients who have this high-leptin state,” Sharma says.

This research was funded by the Breast Cancer Research Foundation and The Fetting Fund.

Learn more about Dipali Sharma’s research, and the work of our other nationally-recognized physician-scientists in developing new ways to diagnose, treat and support breast cancer patients, at the Kimmel Cancer Center’s Breast Cancer Program’s website.

 

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Julie Brahmer

Julie Brahmer, M.D., is interviewed at the ASCO 2016 meeting.

Julie Brahmer, M.D., director of the Thoracic Oncology Program, began treating patients with immunotherapy drugs nearly a decade ago. She led one of the first large studies of the popular drugs, which was reported in 2012. Since then, Brahmer, a program leader in the Bloomberg-Kimmel Institute for Cancer Immunotherapy, has become an expert in identifying and managing side effects that come with taking the drugs. “Patients can experience side effects that include anything that ends in –itis,” says Brahmer. They are typically ones that involve inflammation, such as colitis (inflammation of the colon) and the worst of them, pneumonitis (inflammation of the lungs). These types of side effects aren’t unexpected, says Brahmer, when taking medicines that tinker with the immune system, and inflammation is considered an immune-related biochemical process. Aside from inflammation-related side effects, fatigue often tops the list of the drugs’ side effects, says Brahmer. She says some patients also experience low thyroid hormone levels. A new study of patients receiving immunotherapy at the Kimmel Cancer Center may reveal a connection between the drugs and the development of inflammatory arthritis.

“Patients are concerned about drugs’ side effects,” says Brahmer. “So, we need to educate clinicians and learn to recognize and treat side effects early.” The toxic effects of the drugs can occur anytime during a patient’s regimen, she says, even after patients stop taking the drugs. If side effects occur, they are typically at low grade levels, but some have more severe effects. Treatment includes oral corticosteroids, and, for severe problems, hospitalizations may be necessary.

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Dr. Tom Smith at #ASCO16.

Dr. Tom Smith at #ASCO16.

Tom Smith, M.D., wants cancer patients to live well. Fewer side effects, better quality of life, more joyful time with family…these are among the primary goals, he says, of palliative medicine. Researchers have studied the impact of palliative medicine programs on patients’ outcomes, and results show that patients benefit, says Smith. “A lot of aggressive chemotherapy is given in the last six months of life, and only about 18 percent of these patients ever use hospice, so they are missing an important part of good cancer care.” says Smith, director of Palliative Medicine at Johns Hopkins Medicine and the Harry J. Duffey Family Professor of Palliative Care at the Johns Hopkins Kimmel Cancer Center. Professional organizations, including the American Society of Clinical Oncology (ASCO), have pointed to better treatment outcomes among patients who have six months or less to live and are in hospice programs. “They have better quality of life, better caregiver support and at least two studies have shown that cancer patients who use hospice live longer than those who don’t. There are multiple studies that show cancer patients who get palliative care alongside their usual care have better quality of life, fewer symptoms, can plan better, and live longer, too,” says Smith, who discussed an #ASCO16 presentation  by researchers at the University of North Carolina, Chapel Hill.

So, how can more patients access palliative medicine programs? Smith says the concept of palliative medicine should be introduced early in cancer care -- for every patient -- through consultations with palliative medicine teams, apart from the primary oncologist. Smith suggests GetPalliativeCare.org for more information and PrepareForyourCare.org for tips on how to manage serious illness. He also says that doctors should encourage the concept of “prognostic awareness” sooner than later with their patients, by having specific and honest discussions about prognosis throughout their care.

Watch Smith discuss end of life care in this MedPage Today video and read his comments on the American Association for Cancer Research blog.

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IMG_0625

Suzanne Topalian

Immunotherapy expert, Suzanne Topalian, M.D., delivered a presentation to a standing room only crowd at the 2016 American Society of Clinical Oncology (#ASCO16) regarding new directions in scientists’ search for biomarkers that identify patients and tumor types most likely to respond to immunotherapy drugs. Among the approaches is an immunohistochemistry test for the protein PD-L1, which is found on the surface of cancer cells. PD-L1 binds with its partner, PD-1, a protein found on immune cells, to create a chemical “handshake” that blocks the immune system from identifying and killing cancer cells. Several immunotherapy drugs against PD-1 or PD-L1, called “immune checkpoint blockers,” aim to disrupt this chemical connection. A chemical test performed on biopsy specimens identifies patients whose tumor cells are studded with the PD-L1 protein and may be more likely to respond to checkpoint blocking drugs.  However, there are still many patients whose tumor test for the PD-L1 protein are negative and can respond to the drugs. “This is a complex biomarker,” said Topalian, associate director for the Bloomberg-Kimmel Institute for Cancer Immunotherapy. “There are different interpretations and scoring of the commercially available tests and other tests in development, and more study is needed.”

Another response-predicting biomarker targets mutations in DNA mismatch repair genes found in cancer cells. The connection between the mismatch repair gene mutations and response to the immunotherapy drug pembrolizumab (anti-PD-1) was first described at last year’s ASCO meeting. From that research, scientists at the Kimmel Cancer Center showed that patients whose tumors have these mutations (about 10-15 percent of colorectal cancers and 2-4 percent of other cancer types) are more likely to respond to pembrolizumab. Topalian said last year’s data are holding up and tumor responses occur in about 50 percent or more of patients with these mutations.

Finally, scientists have some of the first evidence, based on data presented earlier this year by Topalian and colleagues at the Fred Hutchinson Cancer Research Center, that patients who have virus-linked skin cancer called Merkel cell carcinoma may also respond well to receiving the immunotherapy drug pembrolizumab (anti-PD-1) as their first therapy. Additional data presented by Howard Kaufman from Rutgers at #ASCO16, showed that among 88 patients with this rare but aggressive form of skin cancer, 32 percent of them had significant tumor regressions after receiving an immunotherapy drug called avelumab (anti-PD-L1), and most of the responses were ongoing at the point of the data’s analysis. Patients who had had two or more previous therapies did not respond as well as those who had only one round of chemotherapy. Taking this and the previous study into context, Topalian noted that these two immunotherapy drugs target the same pathway and seem to mediate regressions in advanced Merkel cell cancers. She said there may be more of an advantage in using these drugs in the first line of therapy for these cancers, however, more observation of patients and additional studies will be needed to provide evidence. For Merkel cell carcinoma, a rare cancer that is classified as an orphan disease, Topalian added, “these two national and global studies highlight the importance of networking centers.”

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With recent FDA approvals of immunotherapy drugs for kidney and bladder cancer, patients now have more options to consider among their treatments. The 2016 ASCO annual meeting featured several new developments in these two cancers that seem to keep the momentum moving forward in this field. We asked Charles Drake, M.D., Ph.D., associate director of the Bloomberg-Kimmel Institute for Immunotherapy at Johns Hopkins, to discuss the significance of the findings.

Following the recent FDA approval of an immunotherapy drug called atezolizumab, which targets a molecule called PD-L1, for second-line treatment of advanced bladder cancer, scientists revealed data from another clinical trial of the drug: Results from a phase II study investigating the PD-L1 inhibitor atezolizumab as first-line therapy for patients with advanced bladder cancer who cannot safely undergo standard therapy (Abstract LBA4500).  In the trial, atezolizumab was given to bladder patients who were not healthy enough to receive conventional high-dose chemotherapy. So, the patients in the trial were given atezolizumab as a so-called first-line therapy. He said, “The response rate in these patients was actually quite good – in the range of about 25 percent.” It’s important, he says, because it gives a good option for these patients. In addition, he says immunologists have long questioned whether checkpoint blockade drugs would work as a first-line treatment as effectively as second or third-line treatments. Moving forward, he says the findings are important for providing bladder cancer patients who are medically ineligible for conventional chemotherapy a new treatment option with a good response rate. With additional clinical trials, Drake’s hope is that scientists will find a “chemo-free” regimen for bladder cancer patients. David McConkey, Ph.D., director of the Johns Hopkins Greenberg Bladder Cancer Institute, also commented on the FDA's approval of "atezo" for second-line treatment of bladder cancer. Watch Drake's video commentary.

Also at #ASCO16, kidney cancer experts will be presenting long-term follow up data on the effectiveness of the immunotherapy drug nivolumab as second-line treatment for kidney cancer patients. Long-term overall survival (OS) with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I and II studies.

Drake, a co-author on the study, says that the data shows favorable outcomes for these patients, specifically that there is a one in three chance that a patient taking this drug in the second line of treatment will be alive 2, 3 and 4 years from now. The scientists also looked at the rate of adverse events over time and whether patients develop long term, autoimmunity-related side effects (which includes arthritis, colitis or pneumonitis). Drake says that the findings are encouraging that there was no indication of long-term autoimmunity-related side effects. He says most of the side effects occur within the first three to six months. Watch Drake's video commentary.

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David McConkey

David McConkey, Ph.D.

A new immunotherapy drug -- the first in its class -- was approved by the Food and Drug Administration last week for bladder cancer. We asked David McConkey, Ph.D., director of the Johns Hopkins Greenberg Bladder Cancer Institute, to explain the significance of this milestone:

"The approval of atezolizumab is arguably the most transformative thing that has happened in our field since the development of cisplatin-based combination chemotherapy over three decades ago.  (In fact, the transformation actually started with the first high profile reports of major clinical activity almost two years ago.)   We had no targeted agents and nothing meaningful to offer patients who had progressed after cisplatin-based therapy.   Investigators and their industrial partners are now developing and/or performing trials with these agents in every disease state.  An important question is whether combinations of atezolizumab and other immune-active agents will produce even greater clinical activity. There is also a pressing need to develop better biomarker-based clinical tools to identify the patients who will obtain the most benefit from these drugs.

The recognition that atezolizumab and other immune checkpoint inhibitors are clinically active has also had a strong beneficial side-effect by rekindling industrial interest in developing other targeted agents in bladder cancer.  For example, we are seeing renewed interest in developing FGFR inhibitors for patients whose tumors contain activating FGFR3 mutations.  These mutations are found in a significant fraction of muscle-invasive cancers (15-20%) and the majority (almost 80%) of non-muscle invasive cancers.  Importantly, the published data from the Phase II atezolizumab trial (Rosenberg et al, Lancet 2016) suggested that the patients whose tumors belonged to the subset of tumors that is enriched with these mutations (“papillary,” TCGA cluster I)  also obtained the least benefit from immune checkpoint blockade.  Therefore, FGFR inhibitors could prove to be active in patients whose tumors are resistant to atezolizumab.  There are a lot of other attractive candidate biological targets in bladder cancers, so hopefully this interest in checkpoint blockade will translate into a strong interest in developing better therapies for bladder cancer overall."

Stay tuned for more developments in bladder cancer. Watch a patient education seminar.

What do you think of this new drug approval?

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This past weekend, the Avon Foundation held its 14th annual event in Washington, D.C. to raise funds for breast cancer research and education. More than 1,900 participants from 41 states and Washington, D.C. walked 39.3 miles in the AVON 39 The Walk to End Breast Cancer. Of the total $4.8 million raised during the weekend event, the Johns Hopkins Kimmel Cancer Center was awarded $750,000 for research, patient navigation and a retreat for metastatic breast cancer patients. Kimmel Cancer Center scientist Sara Sukumar, Ph.D., won a $300,000 grant to study a gene called HOXA5, which acts as a tumor suppressor in normal breast cells. She'll study what goes awry in the gene to lift the brakes on tumor suppression, making breast cells turn cancerous. Josh Lauring, M.D., Ph.D., and Sukumar, who are members of the Breast Cancer Program, accepted the awards at the event. Were you at the event? Tell us your story.

Breast Cancer Program members Josh Lauring and Sara Sukumar accept Avon Foundation awards

Breast Cancer Program members Josh Lauring and Sara Sukumar accept Avon Foundation awards

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In today's lineup of stories covered by WNYC's radio program The Takeaway, Kimmel Cancer Center expert Josh Lauring, M.D., Ph.D., provides his perspective on a new study published yesterday in the journal Nature by the Wellcome Trust Sanger Institute. The study is an analysis of the genomic sequencing of 560 breast cancer patients. Listen to Lauring and radio host John Hockenberry discuss the study:

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At the 2016 American Association for Cancer Research annual meeting today, scientists presented their results of a follow-up study tracking the survival of metastatic melanoma patients who were treated with the immunotherapy drug nivolumab. The drug is currently approved by the U.S. Food and Drug Administration for advanced lung and kidney cancers and advanced melanomas.

Results published in 2014, by a group led by Suzanne Topalian, M.D. professor at the Johns Hopkins Kimmel Cancer Center and associate director for the Bloomberg~Kimmel Institute for Cancer Immunotherapy, showed the first hints that nivolumab could produce lasting, increased survival among patients with metastatic melanoma.

Today’s presentation, also co-authored by Topalian, shows an overall survival rate of 34 percent after four and five years among 107 patients with advanced melanoma who were treated with nivolumab. Typically, the relative five-year survival rate of patients with metastatic melanoma is approximately 16 percent.  In other research, long-term survival rates of metastatic melanoma patients who received another type of immunotherapy drug, called ipilimumab, were reported as approximately 21 percent.

Nivolumab aims not to kill cancer cells directly, but to block a pathway that shields tumor cells from immune system components that are potentially able and poised to fight cancer. The pathway includes two proteins called programmed death-1 (PD-1), expressed on the surface of immune cells, and programmed death ligand-1 (PD-L1), expressed on cancer cells. When PD-1 and PD-L1 join together, they form a biochemical shield protecting tumor cells from being destroyed by the immune system.

“This is the longest follow up for any anti-PD-1/PD-L1 trial,” says Topalian. “We’re encouraged by the long-term survival data.  Our next steps are to find ways to combine immunotherapy with other treatments to push survival rates even higher, and continue studying the biology of tumors to learn why certain patients with cancer respond to immunotherapy and others do not.”

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Kristin Franchesci

Kristin Franceschi competes in a ballroom dancing event.

***Note: This is the final post of a four-part feature story, written by Elizabeth Huebeck. Read part one on Kristin's story, part two on cancer as a chronic disease and part three on Kristin's strategies for staying the course.

Regardless of which treatment path cancer patients take, painful and uncomfortable side effects cannot be avoided. How well therapies are tolerated often depends largely on patients’ overall health before and while battling cancer.

“My pulmonary function is more robust now than before my third lung surgery,” said Kristin. She attributes this improvement to lifting weights after her surgery, a strategy suggested by a member of her healthcare team to ensure optimal strength of her chest wall.

That’s just one way Kristin has made her health a priority during her cancer journey. In addition, she has relied on yoga for rehab after all three of her lung surgeries. She ardently watches her diet. And she has adopted meditative practices, which she says have been incredibly helpful during stressful times, like when she’s waiting on the table to get a scan, sitting in the waiting room, or about to go into surgery.

All these suggestions point to the same mantra that has helped see Kristin through the last five years: “The healthier you are, the better you’re going to be able to survive,” she said.

Kristin says that, right now, she feels great. But she also knows that at any point in the future, she may learn from a CT scan that her cancer has re-emerged. “You just have to take one day at a time. Put one foot in front of the other,” she says. Fitting advice from a ballroom dancer.

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