Steve Baylin, Elizabeth Jaffee and Bill Nelson.

Steve Baylin, Elizabeth Jaffee and Bill Nelson.

Johns Hopkins Kimmel Cancer Center researchers and clinicians are among the leaders of one of the 10 Stand Up To Cancer (SU2C) Catalyst® clinical trial projects. Researchers from more than 30 institutions are collaborating across academic and corporate borders on clinical trials aimed at understanding why treatments are effective—across a variety of cancers—in a program supported by industry. The inaugural SU2C Catalyst projects will explore new uses for an array of powerful medicines, from three SU2C Catalyst Charter Supporters and six other pharmaceutical companies.

Johns Hopkins Kimmel Cancer Center epigenetics expert Stephen Baylin, M.D., is a co-leader of a project with Michael Hellmann, M.D., from Memorial Sloan Kettering Cancer Center. The focus of the collaboration is a clinical trial combining two epigenetic drugs with immunotherapy for patients with non-small-cell lung cancer. Lung cancer experts Jarushka Naidoo, M.B.B.Ch., also from Kimmel Cancer Center, will oversee the trial at Johns Hopkins. The clinical trial comprises work from the Van Andel Research Institute (VARI)–SU2C team co-lead by Baylin and Peter Jones, Ph.D., VARI scientific director.

Epigenetics is the term for cancer-promoting alterations to our genes that occur without permanently marking the DNA of cells like mutations do. In epigenetics, changes in chemical marks on DNA and loosening or tightening of the way DNA is packaged in the nucleus of the cell cause genes to be turned on and off. Cancer corrupts this normal cellular function to allow cancers to begin, grow and spread.

The SU2C-supported clinical trial is based largely on the soon-to-be published laboratory research of Kimmel Cancer Center graduate student Michael Topper and research associate Michelle Vaz. It will use two drugs, guadecitabine and mocetinostat, to block both kinds of epigenetic alterations in combination with pembrolizumab, an immunotherapy that tears down a shield that cancer cells use to hide from the immune system.

“We hope this combined treatment will expand the benefit of immunotherapy to more non-small-cell-lung cancer patients,” says Baylin, the Virginia and D.K. Ludwig Professor of Oncology and Medicine, Co-Director of the Kimmel Cancer Center’s Cancer Biology Division and Associate Director for Research Programs.

The Johns Hopkins Kimmel Cancer’s Greenberg Bladder Cancer Institute is also a site for a Van Andel Research Institute–Stand Up To Cancer Epigenetics Dream Team

bladder cancer trial that will investigate whether epigenetic drugs can reverse resistance to immunotherapy, a problem that approximately 85 percent of patients with the disease face. Noah Hahn, M.D., is leading the trial at the Kimmel Cancer Center.

Currently, about 20 percent of patients get long lasting control of their lung cancer with immunotherapy alone, but Baylin, Hellmann and team think they may be able to increase the number of patients who respond by adding epigenetic-targeted treatments. “This clinical trial will tell us if epigenetic therapy can make immunotherapy work better in these patients who do not get results from immunotherapy up front.”

Read the full announcement and an announcement from the Van Andel Research Institute. Learn more about other SU2C-supported cancer clinical trials at StandUpToCancer.org and aacr.org.

 

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--Two clinical trials suggest promise for using these medications in combination with other cancer therapies

Two clinical trials using combinations of drugs meant to change cancer epigentics —or the way tumors express genes — failed at shrinking colon and breast tumors. However, these trials open the door for others currently in the works to combine epigenetic therapies with chemotherapy, immunotherapy and other treatments that could be more successful, Johns Hopkins researchers report in two new studies.

Cells operate using instructions not only from the four nucleotides that make up DNA, but also from so-called epigenetic, or “above the genome,” modifications — molecules that attach to DNA or to proteins that closely interact with this genetic molecule to switch genes off or on. For example, methyl groups that attach to genes can turn them off, preventing them from producing proteins. Histone deacelytalses, which remove molecules that attach to the protein “spools” that DNA coils around and allows DNA to coil more tightly, can also dampen gene expression.

Scientists have long known that cancer cells tend to express DNA abnormally because of epigenetic changes, particularly those that affect genes that would normally suppress tumors or allow them to be attacked by the immune system, explains Nita Ahuja, M.D., professor of urology, surgery and oncology at the Johns Hopkins University School of Medicine. However, she adds, lab work in cells and animal models of cancer has suggested that drugs that remove these abnormal epigenetic marks could be effective cancer treatments.

“It’s very hard to change someone’s DNA. It’s the hardware of the cell. But epigenetics is the software. It has some plasticity to it,” says Ahuja. “It’s been the dream for many of us in this field that we could harness that plasticity to treat cancer.”

While one epigenetic therapy, 5-azacitidine, has already been approved to treat a group of cancers involving the bone marrow and blood known as myelodysplastic syndrome, single epigenetic therapies haven’t shown promise for solid tumors such as those in colon cancer. Thus, Ahuja, fellow study leader Nilofer Azad, M.D., associate professor of oncology at the Johns Hopkins University School of Medicine, and colleagues launched a multi-institutional study to test two different epigenetic therapies on colon cancer in combination: 5-azacitidine, which removes DNA methylation, and entinostat, which inhibits histone acetylation.

The trial, detailed in the Feb. 5, 2017, Oncotarget, enrolled 47 colon cancer patients from April 2010 to December 2011, all of whom had failed multiple lines of traditional cancer treatments and had few options left. Thirty-seven of these patients underwent tumor biopsies before they started treatment, which involved subcutaneous shots of 5-azacitidine and taking entinostat orally. After two months of therapy, 18 of these patients underwent a second tumor biopsy.

Few patients had concerning side effects, suggesting that these drugs were safe to administer. Analyses of the collected tissue showed that the drugs reduced DNA methylation in 13 of these patients. However, none of the 47 experienced any shrinkage of their tumors, the primary goal of the study, says Azad. “Overall, this is a negative trial. We didn’t meet our primary endpoint,” she says.

However, she says, the fact that these drugs did appear to positively affect DNA methylation in the majority of patients suggests that epigenetic therapies could be effective in combination with other cancer therapies. For example, some cancers develop a resistance to chemotherapy or other treatments over time, an effect likely due to epigenetic changes. By removing epigenetic marks, these tumors might become susceptible to treatments they resisted before.

A second team of researchers, led by Vered Stearns, M.D., professor of oncology at the Johns Hopkins University School of Medicine, and Roisin M. Connolly, M.D., assistant professor of oncology at the school of medicine, tested this strategy in breast cancer patients in a trial detailed online on Dec. 15, 2016, in Clinical Cancer Research. The team launched a multicenter study that gave the same epigenetic drug combination to 40 breast cancer patients. Twenty-seven of these had a subtype called hormone-resistant breast cancer, and thus didn’t respond to commonly used hormone-blocking medications that can prevent cancer growth. Another 13 patients had triple-negative breast cancer, a subtype that’s known to be particularly aggressive and has few treatment options. Like the colon cancer patients in the other trial, each of these 40 breast cancer patients had failed multiple lines of treatment.

Similar to the patients in the colon cancer trial, 95 percent of those in the breast cancer trial had pre-treatment biopsies, then 60 percent of these underwent a subsequent biopsy after two months of treatment. Tissue analyses showed that the majority of these patients also had reduced DNA methylation. However, unlike the colon cancer trial, a single patient in the hormone-resistant group experienced significant tumor shrinkage.

As cancers in other hormone-resistant patients began to progress, the researchers offered them the option to restart hormone-blocking therapy, an idea that they thought might have positive results if the epigenetic therapies had removed methylation responsible for hormone resistance. Sure enough, a second patient experience significant tumor shrinkage after starting this protocol.

The fact that even two patients experienced positive outcomes on this trial is a promising start, says Stearns. “We need to go back to the lab and get a better understanding of these tumors and their biology to figure out which subset of patients is most likely to benefit from these treatments,” she says. “Even though we didn’t meet the endpoints that were prespecified for this study, we’ve generated several really interesting hypotheses that could lead to more effective treatments for some patients in the future.”

One of those hypotheses, says Connolly, is that epigenetic therapies appear to take significantly longer to work than traditional cancer chemotherapies. “There’s a suggestion that maybe with longer treatment, particularly with adding hormone-blocking therapy or other agents, a larger population of patients might benefit.”

She and the other researchers are also planning to test combining these medications with immunotherapies, cancer treatments that have shown limited success for some tumor types and no success for others. By “hitting the reset button” for tumor cells with epigenetic therapies, Connolly says, researchers may be able to significantly increase the response rate for immunotherapy treatments.

Both trials were funded by Stand Up to Cancer, a program of the Entertainment Industry Foundation, administered by the American Association for Cancer Research (AACR). The colon cancer trial received additional funding from the AACR Jeanette Littlefield Grant, the Conquer Cancer Foundation and the Mayo Clinic-Phase II Consortium grant N01-CM-2011-00099. The breast cancer trial received additional funding from the Cancer Therapy Evaluation Program, National Cancer Institute (grants MCR-0019-P2C, U01 CA070095 and UM1CA186691); Specialized Programs of Research Excellence in Breast Cancer (P50 CA88843), the Microarray Core (NIH grants P30 CA006973) and Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH grants P30 CA006973 and UL1 TR 001079), the Shared Instrument Grant (1S10RR026824-01), the Clinical Protocol and Data Management facilities (P30 CA006973 and P30CA 047904) and the Bioinformatics Core (P30 CA006973), the Pennsylvania Department of Health, QVC and Fashion Footwear Association of New York (FFANY), the Cindy Rosencrans Fund for Triple Negative Breast Cancer Research, and Lee Jeans and the Entertainment Industry Foundation.

Other Johns Hopkins researchers who participated in the colon cancer trial include Anup Sharma, Thomas Brown, Prakriti Medvari, Hariharan Easwaran, Ihab Kamel, Ross Donehower and Stephen Baylin. Other Johns Hopkins researchers who participated in the breast cancer trial include Huili Li, Zhe Zhang, Michelle A. Rudek, Stacie C. Jeter, Shannon A. Slater, Penny Powers, Antonio C. Wolff, John H. Fetting, Nita Ahuja, Leslie Cope, Stephen B. Baylin and Cynthia A. Zahnow.

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Patients with advanced cancer should see a dedicated palliative care team composed of a doctor, advanced practice nurse, social worker and chaplain starting early in their diagnosis, according to guidelines issued by the American Society of Clinical Oncology (ASCO), says the Johns Hopkins doctor who is the senior author.

These guidelines, say Thomas J. Smith, M.D., professor of oncology and the Harry J. Duffey Family Professor of Palliative Medicine at the Johns Hopkins University School of Medicine and Kimmel Cancer Center, got their start after a 2010 study published in the New England Journal of Medicine. That study followed 151 patients with metastatic non-small cell lung cancer. Roughly half received the usual care for this disease, and half received the usual care plus regular care from a multidisciplinary palliative care team starting by eight weeks after diagnosis. The study authors reported that, compared to those in the usual care group, those in the palliative care group had about half the rate of depression and anxiety, a better understanding of their prognosis and better symptom control, plus they tended to live longer and used fewer medical resources.

Based on these findings and a growing number of other studies with similar results for other types of cancers, ASCO published provisional recommendations in 2012 suggesting that patients with advanced cancers should receive similar palliative care. However, says Smith, with the number of strong studies with similar findings now totaling more than a dozen, he and other members of an expert team — including cancer doctors, nurses, social workers, researchers and patient advocates — came together to develop a set of guidelines that can help shape how medicine is practiced across the country.

Smith explains that evidence from these previous studies shaped the new guidelines. These call for advanced cancer patients to be cared for not only by their oncologists and primary care physicians but also by a team that includes a palliative medicine doctor, who is specially trained to help patients understand their prognosis and treatment options; an advanced care nurse, such as a nurse practitioner, who can help patients and their families manage symptoms and other medical concerns; a social worker, who can counsel patients and their families on adapting to a serious illness and work on advanced planning, such as developing a health care directive, appointing a durable power of attorney or planning a hospice visit; and a chaplain, who can help provide spiritual care or find meaning at the end of life.

“Each member contributes something important,” Smith says.

Because previous studies suggested that palliative care is most efficacious when started early, he adds, the guidelines call for a patient’s first visit with this team to be less than eight weeks after diagnosis.

And, the benefits of palliative care are not just for people who might die of their disease. Even bone marrow transplant patients and their families benefit.

Many oncologists aim to provide these services through their offices, Smith explains. However, with the bulk of their time spent simply managing patients’ oncology treatments, the palliative care that many patients need falls through the cracks.

Currently, he says, many hospitals lack the resources to meet these guidelines — palliative medicine is a relatively new specialty, thus the ranks of dedicated practitioners remain small — but these strong recommendations, made with a wealth of research showing numerous benefits to patients, will encourage hospitals to build teams. “We recognize that not everyone has access yet to high quality palliative care,” Smith says, “but we should be addressing that and working on it.”

And ask your Johns Hopkins oncologist if you can see the palliative care team.

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Palliative care isn’t just for cancer patients. The palliative care team can support your family and caregivers as well as you during your cancer treatment. Our expert team can provide your family and caregivers:

  • A communication bridge to facilitate communication between you, your family and your treatment team;
  • Relief for the stress, worry and sadness they may be experiencing about your illness;
  • Spiritual and emotional support as they accompany you on your journey;
  • Help with your insurance, Social Security and other paperwork.

You can ask your doctor or nurse about seeking palliative care support for your family caregivers. Learn more about the palliative care options in this video:

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While pain relief is important, relief of other symptoms such as nausea, fatigue and shortness of breath also may be a part of your palliative care. You might seek palliative care for emotional, social or spiritual support, rather than for your physical pain or symptoms. Care teams include experts such as physicians, nurses, social workers and a chaplain, so that you receive the full range of palliative care options during your cancer treatment.

The palliative care team can work with you to communicate what you are feeling and experiencing to your treatment team.  Learn more about palliative care in this video:

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When you’re a cancer patient, every day matters. To ease your symptoms and stress, you may receive palliative care, if appropriate, right from the time of your diagnosis. You also can ask your doctor or nurse for your palliative care options at any point during your treatment, since palliative care can be coupled with curative treatment.

You may want to seek palliative care to help manage your pain, to receive social and emotional support or for spiritual support. Your family and caregivers also may want to seek support from our palliative care team. The team also can help you communicate with your treatment team about your pain and other symptoms, serving as a communications bridge for you.

Learn more about the palliative care options in this video:

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When you’re considering palliative care as part of your cancer treatment, consider these criteria for deciding whether it’s right for you.

  • How severe is your illness? Palliative care addresses serious or chronic diseases, such as cancer, HIV/AIDS, and Alzheimer’s, among many other diseases.
  • Do you need emotional, physical or spiritual support? Palliative care isn’t just for easing pain, although managing pain can be an important component of this care. You also may want to seek palliative care for emotional, social or spiritual support.
  • Does your family need support? At the Johns Hopkins Kimmel Cancer Center, palliative care supports your family members as well as patients during your cancer journey.

Learn more about the palliative care options in this video:

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According to experts at the Johns Hopkins Kimmel Cancer Center, palliative care is “ease without curing.” Its focus is improving the quality of life for seriously ill patients, helping you to carry on with your daily life while you undergo treatment, and helping you tolerate medical treatments.

Palliative care includes three key approaches:
• pain and symptom management, for the full range of reactions—physical, spiritual, social and emotional--you may be having to your cancer and its treatment;
• communication to help you feel comfortable communicating with your treatment team about your pain and symptoms, and
• coordinated care, so that your palliative care works with your treatment.

Learn more about palliative care in the following video and about services offered through The Harry J. Duffey Family Patient and Family Services Program.

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If you’re a cancer patient, you should apply for disability benefits as soon as you become disabled, according to social workers at the Johns Hopkins Kimmel Cancer Center. .  It can take months to process your application for either Social Security Disability or Supplemental Security Income. The Social Security Administration's eligibility screening tool is available online.

If you apply and are turned down for these benefits, you have 60 days from the date you were denied benefits to appeal the process. Use this website to learn how to file an appeal, or call your local Social Security office. You may want to consider hiring a lawyer to make the appeal, or asking a friend or family member to advocate in your behalf.

Find more useful resources in our Patient and Family Education pages.

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Supplemental Security Income guidelines are set by the federal government for all 50 states, according to social workers at the Johns Hopkins Kimmel Cancer Center. Income may include your wages, Social Security benefit payments, and pensions. It also includes resources like real estate, bank accounts, cash, stocks and bonds, and food and shelter. Your total monthly income, and where you live, can help determine how much of this benefit you can receive.

Our clinical social workers are available to assist cancer patients undergoing treatment at the Kimmel Cancer Center with disability applications, loss of insurance, COBRA, disability discrimination, and other issues.

Find more useful resources in our Patient and Family Education pages.

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