Deadly Lung Cancers Are Driven by Multiple Genetic Changes

Blood-Based Cancer Tests Reveal Complex Genomic Landscape of Non-Small Cell Lung Cancers

A new UC San Francisco–led study challenges the dogma in oncology that most cancers are caused by one dominant “driver” mutation that can be treated in isolation with a single targeted drug. Instead, the new research finds one of the world’s most deadly forms of lung cancer is driven by changes in multiple different genes, which appear to work together to drive cancer progression and to allow tumors to evade targeted therapy.

These findings — published online on November 6, 2017 in Nature Genetics — strongly suggest that new first-line combination therapies are needed that can treat the full array of mutations contributing to a patient’s cancer and prevent drug resistance from arising.

“Currently we treat patients as if different oncogene mutations are mutually exclusive. If you have an EGFR mutation we treat you with one class of drugs, and if you have a KRAS mutation we pick a different class of drugs. Now we see such mutations regularly coexist, and so we need to adapt our approach to treatment,” said Trever Bivona, MD, PhD, a UCSF Medical Center oncologist, associate professor in hematology and oncology, and member of the Helen Diller Family Comprehensive Cancer Center at UCSF.

Lung cancer is by far the leading cause of cancer death worldwide. Efforts to identify the genetic mutations that drive the disease have led to targeted treatments that improve life expectancy for many patients, but these drugs produce temporary remission at best — sooner or later, cancers inevitably develop drug resistance and return, deadlier than ever.

The new UCSF-led study — which analyzed tumor DNA from more than 2,000 patients in collaboration with Redwood City–based Guardant Health — is the first to extensively profile the genetic landscape of advanced-stage non–small cell (NSC) lung cancer, the most common form of the disease.

“The field has been so focused on treating the ‘driver’ mutation controlling a tumor’s growth that many assumed that drug-resistance had to evolve from new mutations in that same oncogene. Now we see that there are many different genetic routes a tumor can take to develop resistance to treatment,” said Bivona, who is also co-director of a new UCSF-Stanford Cancer Drug Resistance and Sensitivity Center funded by the National Cancer Institute. “This could also explain why many tumors are already drug-resistant when treatment is first applied.”

Scientists make a major breakthrough to treat fibrotic diseases that cause organ failure

Researchers from Duke-NUS Medical School (Duke-NUS) and the National Heart Centre Singapore (NHCS) have discovered that a critical protein, known as interleukin 11 (IL11) is responsible for fibrosis and causes organ damage. While it is surprising that the importance of IL11 has been overlooked and misunderstood for so long, it has now been very clearly demonstrated by this work.

A protein known as transforming growth factor beta 12 (“TGFB1”) has long been known as the major cause of fibrosis and scarring of body organs, but treatments based on switching off the protein have severe side effects. The scientists discovered that IL11, is even more important than TGFB1 for fibrosis and that IL11 is a much better drug target than TGFB1.

Fibrosis is the formation of excessive connective tissue, causing scarring and failure of bodily organs and the skin. It is a very common cause of cardiovascular and renal disease, where excessive connective tissue destroys the structure and function of the organ with scar tissue. Compared to other Asians, American, and Europeans, Singaporeans have a higher prevalence of coronary artery disease, hypertension, and diabetes, the three most common diseases that lead to heart failure. In addition, kidney failure is an epidemic in Singapore and around the world. Fibrosis of the heart and kidney eventually leads to heart and kidney failure, thus this breakthrough discovery — that inhibiting IL11 can prevent heart and kidney fibrosis — has the potential to transform the treatment of millions of people around the world.

The international team, led by Professor Stuart Cook, Tanoto Foundation Professor of Cardiovascular Medicine, along with Assistant Professor Sebastian Schäfer, both from NHCS and Duke-NUS’ Programme in Cardiovascular and Metabolic Disorders, carried out the translational research to identify the key drivers of chronic fibrotic disease in heart, kidney, and other tissues. The team also includes researchers from Harvard University and University of California, San Diego/UCSD (USA), Max Delbrück Center for Molecular Medicine/MDC-Berlin (Germany), London Institute of Medical Sciences/MRC-LMS and Imperial College London (the UK), and the University of Melbourne (Australia).

“Fibrotic diseases represent a major cause of illness and death around the world. The discovery that IL11 is a critical fibrotic factor represents a breakthrough for the field and for drug development. It is an incredibly exciting discovery,” explained the study’s senior author, Professor Cook, who is also Director, National Heart Research Institute Singapore.

“Currently, more than 225 million people worldwide suffer from heart and kidney failure and there is no treatment to prevent fibrosis. The team is at the stage of developing first-in-class therapies to inhibit IL11 and this offers hope to patients with heart and kidney disease,” shared Professor Terrance Chua, Medical Director, National Heart Centre Singapore.

“This therapeutic target for fibrotic diseases of the heart, kidney and other organs may be exactly what we need to fill the unmet pressing clinical gap for preventing fibrosis in patients. We are proud to announce that the suite of intellectual property arising from this research has been licensed to a newly launched Singapore-funded biotechnology start-up Enleofen Bio Pte Ltd, which is co-founded by Professor Cook and Assistant Professor Schäfer,” said Professor Thomas Coffman, Dean of Duke-NUS Medical School.

Trained T-Cells to Target Toxic Viruses in Pediatric Patients New Cellular Therapy Approach for Children with Compromised Immune Systems

Michael Pulsipher, MD, of the Children’s Center for Cancer and Blood Diseases at Children’s Hospital Los Angeles, along with Michael Keller, MD from Children’s National Health System in Washington, DC, have been awarded $4.8 million by the California Institute for Regenerative Medicine (CIRM) to study the use of a new T-cell therapy to help fight active viral infections in children with severe immune deficiencies. In what will be the largest multi-center pediatric clinical trial of this kind to date, investigators will test the feasibility of using “viral specific” T-cells that are engineered to target three common and potentially toxic viruses: Epstein-Bar virus (EBV), cytomegalovirus (CMV) and adenovirus.

In healthy individuals infections with EBV, CMV and adenovirus cause fatigue, sore muscles, sore throat and swollen glands, but after a short period they recover. For children with weakened immune systems, however, infection with these viruses can lead to severe organ damage or death.

“When patients have severe inherited immune deficiencies or are intensely immune suppressed after a bone marrow transplant, standard antiviral medications are sometimes not enough and patients can die from common viral infections,” explained Pulsipher. “Patients often need at least some function of their own immune systems in addition to antiviral medications in order to clear these infections, but sometimes the patient’s own T-cells are not up to the task.”

Previous studies have demonstrated success in restoring immunity against a particular virus by using donor T-cells that are engineered to target a specific virus for therapy following BMT.

For the new clinical trial, Pulsipher, Keller and their collaborators will use T-cells from healthy donors that have been trained and expanded to target the viruses, then preserved in a donor “bank” for use in the trial. The cells are then individually matched to specific patients based upon their genetic make-up and the viral infection they are experiencing, and shipped to individual centers for infusion. After infusion, the virus-specific targeted T-cells can not only control the active infection, but can help prevent other infections.

“It is our hope that with these trained T-cells, we can help the most vulnerable patients fight off life-threatening viral infections,” said Keller. “By offering a ‘donor’ bank, we are significantly expanding the reach of this therapy and increasing access to even more children, which is extremely exciting.”

“Our study design is to use a multi-virus T-cell therapy to reconstitute immunity against all three of these viruses,” said Pulsipher. “Restoring immunity against multiple viruses simultaneously provides patients with protection from severe viral infections and reduces the need for continued prophylaxis with pharmacotherapy drugs after transplant which can have adverse effects.”

The study, which is expected to include up to 30 centers, will be run through the Pediatric Blood and Marrow Transplant Consortium (PBMTC) Operations Center at CHLA and was developed and is being performed in collaboration with the Primary Immune Deficiency Treatment Consortium (PIDTC). Cell manufacturing for use in the clinical trial will be conducted by the Program for Cell Enhancement and Technologies for Immunotherapy (CETI) of the Children’s National Health System.

FDA Announces First Approval of Targeted Therapy Based on Basket Study

Precision medicine clinical trial leads to approval of first treatment for Erdheim-Chester disease

The US Food and Drug Administration (FDA) has announced that it has approved the drug vemurafenib for the treatment of patients with BRAF V600-mutant Erdheim-Chester disease (ECD). This is the first approval of a targeted therapy based on a basket study and the first-ever drug approved for ECD, a rare blood disorder.

This landmark approval came as a direct result of research at Memorial Sloan Kettering Cancer Center (MSK). MSK researchers, led by Physician-in-Chief José Baselga, MD, PhD, pioneered the concept of a basket study, which harnesses the power of precision medicine by assigning treatments to patients based on the genetic alterations driving their cancers rather than where their tumors originated in the body. This approval is based off of the data of 22 ECD patients enrolled in the phase II VE-BASKET study. 

ECD is one of an extremely rare form of blood cancers known collectively as histiocytoses that can lead to life-threatening complications, including damage to the heart, lungs, and kidneys. It’s estimated that there are fewer than 300 cases of ECD in the United States. More than 50 percent of people with ECD have BRAF V600-mutant disease, indicating that they would benefit from this drug. Previous treatments for ECD have included off-label use of chemotherapy, radiation, steroids, and the immunotherapy drug interferon, but all of these have limited efficacy based on anecdotal reports and potentially severe side effects.

Based on the work of MSK medical oncologist Paul Chapman, MD, vemurafenib was previously approved for the treatment of advanced melanoma that carries the BRAF V600E mutation. Dr. Chapman led the phase III trial for vemurafenib that led to the drug’s approval for that disease in 2011. In August 2017, vemurafenib was granted FDA Priority Review and Breakthrough Therapy Designation for the treatment of BRAF V600-mutant ECD.

About the Study

This approval is based on data from the phase II VE-BASKET study, a nonrandomized, histology-independent evaluation of the efficacy of vemurafenib, an inhibitor of BRAF V600 kinase, in non-melanoma cancers, including ECD. This first-in-kind study enrolled participants across multiple diseases, based predominantly on genetic profile rather than where the cancer originated. Initial study results were published in the New England Journal of Medicine in August 2015.

Final results for the 22 people with ECD showed a best overall response rate of 54.4 percent by RECIST v1.1. Importantly, responses and disease control were extremely durable. The median duration of response was not estimable at a median follow-up time of 26.6 months. At two years, 83 percent of patients remained progression free. The safety of vemurafenib in ECD patients was similar to that previously reported in patients with melanoma. The most common adverse events were joint pain, rash, hair loss, fatigue, change in heart rhythm and skin tags. 

Precision Medicine at MSK

Experts at MSK have taken the lead in developing clinical trials for a number of promising treatments that are based on tumors’ mutational profiles. Since August 2015, when MSK experts published initial results of the first basket study, histology-agnostic clinical trials have emerged as one important means of systematically testing a targeted therapy across a variety of tumor types. This innovative clinical trial design helps collect data faster and may accelerate the development of medicines for diseases with high unmet need. Basket studies can include many more people than disease-specific trials, allowing researchers to evaluate multiple diseases simultaneously. This is particularly important for diseases such as ECD that are extremely rare, making it difficult to fully enroll a disease or tumor-specific trial.

MSK leadership saw the promise of precision oncology early on and committed to realizing its ability to create better treatment options for all people with cancer. In 2014, the Marie-Josée and Henry R. Kravis Center for Molecular Oncology (CMO) was established to improve cancer care and research through genomic analysis and MSK-IMPACT™ (Integrated Mutation Profiling of Actionable Cancer Targets) was launched. This powerful diagnostic test provides detailed genetic information about a patient’s cancer that can guide treatment and identify clinical trial opportunities. To date, more than 20,000 MSK patients with advanced cancer have had their tumors sequenced through MSK-IMPACT. Most recently, Dr. Baselga and colleagues published a roadmap to precision oncology in the form of a seminal review paper in Cell.  

Breast cancer researchers track changes in normal mammary duct cells leading to disease

Breast cancer researchers have mapped early genetic alterations in normal-looking cells at various distances from primary tumours to show how changes along the lining of mammary ducts can lead to disease.

The findings of the multidisciplinary team of surgeons, pathologists and scientists led by principal investigator Dr. Susan Done are published online today in Nature Communications. Dr. Done, a pathologist affiliated with The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, is also an associate professor in the Department of Laboratory Medicine and Pathobiology, University of Toronto.

“We have found another piece in the cancer puzzle – knowledge that could one day be used for more precision in screening and breast cancer prevention, and also help with therapeutic approaches to block some of the earliest alterations before cancer develops and starts to spread.”

Lead author Moustafa Abdalla writes: “Almost all genomic studies of breast cancer have focused on well-established tumours because it is technically challenging to study the earliest mutational events occurring in human breast epithelial cells.” Instead, this study found a way to identify early changes that preceded the tumour, enabling better understanding of cancer biology and disease development.

“Normal breast epithelium from the duct giving rise to a breast cancer has not been previously studied in this way.”

Dr. Done explains: “Most breast cancer starts in the epithelial cells lining the mammary ducts. But the breast ducts are complex structures, like the branches of a tree. Guesstimating which duct is close to the tumour is not very accurate. Thanks to our surgeons, we were able to obtain samples along normal-looking ducts close to the nipple and close to the tumour, as well as samples on the opposite side of the same breast to study and compare.”

In the operating room, surgeons inserted a fibre-optic scope through the nipple into the ducts below, and then injected dye into cancerous breasts being removed. This ductoscopy technique enabled the pathologists to identify the exact duct leading to the tumour and subsequently classify genetic alterations either increasing or decreasing as they moved nearer to the cancer.

“Cancer is not a switch that happens overnight. Once a patient notices a lump the tumour has been present for some time accumulating genetic changes. It is difficult at that point to identify the first changes that may have had a role in initiating or starting the cancer,” says Dr. Done.

The research further identified genes that seem to be acting together in groups or pathways. “Some of these genes were either increased or decreased in the area of the tumour, no matter the type of breast cancer, and this is important because within the patterns we identified were predictable alterations. This meant we could determine from the sample where it came from in the breast,” says Dr. Done.

“Our research demonstrated and supports earlier research from elsewhere that changes in cells occur before you can see them. The fact that changes are already present in different regions of the breast could be important in the delivery of radiation therapy or surgical margin assessment. We’re a long way from bringing this into clinic, but it is something we will think about as we continue our research.”

FDA awards 15 grants for clinical trials to stimulate product development for rare diseases

The U.S. Food and Drug Administration today announced that it has awarded 15 new clinical trial research grants totaling more than $22 million over the next four years to boost the development of products for patients with rare diseases. These new grants were awarded to principal investigators from academia and industry across the country.

“Given the often small number of patients facing certain rare diseases, there can be limited resources devoted to researching new drugs and unique challenges with recruiting and conducting the clinical trials needed to develop medicines targeted to rare conditions,” said FDA Commissioner Scott Gottlieb, M.D. “For more than 30 years, the FDA has been committed to investing in trials of potentially life-changing treatments for patients with rare diseases, especially in situations where commercial incentives may not be enough to foster the collection of quality data that can ultimately support efficient development and FDA-approval of treatments for patients who lack effective alternatives. By helping to support the cost of development of these potential new drugs, and reduce some of the financial risk, we also hope that these grants will lower the cost of the capital needed to develop these products, boost competition and translate into lower prices for successful medicines. This can help increase access to resulting therapies.”

The FDA awarded the grants through the Orphan Products Clinical Trials Grants Program, funded by Congressional appropriations, to encourage clinical development of drugs, biologics, medical devices, or medical foods for use in rare diseases. The grants are intended for clinical studies evaluating the safety and effectiveness of products that could either result in, or substantially contribute to, the FDA approval of products targeted to rare diseases.

Approximately 33 percent of the new grant awards fund studies to accelerate cancer research by enrolling patients with rare forms of cancer. Sixty percent of these studies target devastating forms of brain and peripheral nervous system cancers, including glioblastoma and anaplastic astrocytoma. One study recruits children as young as one year old with a particularly aggressive form of neuroblastoma.

Other studies span a broad range of diseases and address unmet needs like treating hyperphagia in Prader-Willi syndrome, a genetic disease that primarily affects children, and idiopathic osteoporosis in premenopausal women. Two studies recruit patients with unmet need in sickle cell disease. In addition, one study evaluates a new combination of existing antibiotics to treat pulmonary tuberculosis (TB), including multidrug-resistant TB. TB is a leading killer of HIV-positive patients, and, though not as common in the United States, one-third of the world’s population is infected with TB.

“The clinical trials grant program is an important part of the FDA’s ongoing commitment to encouraging and supporting the development of safe and effective therapies for rare diseases,” said Rachel Sherman, M.D., M.P.H, FDA’s principal deputy commissioner. “The grants awarded this year will support needed research in a range of rare diseases that have little, or no, treatment options for patients.”

A total of 76 grant applications were received for this fiscal year, with a funding rate of 20 percent. The grant recipients for fiscal year 2017 are the following:

  • AADi, LLC (Pacific Palisades, California), Neil Desai, Phase 2 Study of ABI-009 for the Treatment of Advanced Perivascular Epithelioid Cell Tumors — about $2 million over four years
  • Albert Einstein College of Medicine (Bronx, New York), Caterina Minniti, Phase 2 Study of Topical Sodium Nitrite for the Treatment of patients with Sickle Cell Disease & Leg Ulcers — about $2 million over four years
  • Albert Einstein College of Medicine (Bronx, New York), Eric Hollander, Phase 2 Study of Oxytocin for the Treatment of Hyperphagia in Prader-Willi Syndrome — about $1.5 million over three years
  • Alkeus Pharmaceuticals, Inc. (Cambridge, Massachusetts), Leonide Saad, Phase 2 Study of ALK-001 for the Treatment of Stargardt Disease – about $250,000 over one year
  • CereNova, LLC (Durham, North Carolina), Daniel Laskowitz, Phase 2A Study of CN-105 for the Treatment of Intracerebral Hemorrhage — about $1 million over two years
  • Columbia University Medical Center (New York), Elizabeth Shane, Phase 2 Study of Teriparatide for the Treatment of Idiopathic Osteoporosis in Premenopausal Women — about $1.9 million over four years
  • Columbia University Medical Center (New York), Gulam Manji, Phase 2 Study of PLX3397 + Sirolimus for the Treatment of Malignant Peripheral Nerve Sheath Tumors — $2 million over four years
  • Dana-Farber Cancer Institute (Boston), Steven Dubois, Phase 1 Study of dual PI3K/BRD4 Inhibitor SF1126 for the Treatment of Neuroblastoma — $750,000 over three years
  • Duke University (Durham, North Carolina), Allan Kirk, Phase 2 Study of Belatacept, Alemtuzumab, and Sirolimus in Renal Transplantation — about $1 million over three years
  • Johns Hopkins University (Baltimore), Susan Dorman, Phase 2a Study of Rifampin, Merrem and Augmentin for the Treatment of Pulmonary Tuberculosis — about $2 million over four years
  • New York Medical College (Valhalla, New York), Mitchell Cairo, Phase 2 Defibrotide for the Prevention of Complications in High-Risk Sickle Cell Disease Patients Following Allogeneic Stem Cell Transplantation – about $1.75 million over four years
  • Protalex, Inc (Florham Park, New Jersey), Richard Francovitch, Phase 1/2 Study of PRTX-100 for the Treatment of Immune Thrombocytopenia — about $500,000 over two years
  • Sloan-Kettering Institute for Cancer Research (New York), Ping Chi, Phase 2 Study of MEK162 & Imatinib for the Treatment of Gastrointestinal Stromal Tumors — $2 million over four years
  • Tocagen Inc. (San Diego), Asha Das, Phase 2/3 Study of Toca 511 +Toca FC versus SOC in Recurrent Glioblastoma and Anaplastic Astrocytoma — $2 million over four years
  • University of California, San Francisco (San Francisco), Marshall Stoller, Phase 2 Study of Lipoic Acid for the Treatment of Cystine Nephrolithiasis — about $2 million over four years

Since its creation in 1983, the Orphan Products Clinical Trials Grants Program has provided more than $390 million to fund more than 600 new clinical studies. At least 60 grants have supported the marketing approval of more than 55 orphan products. Three of the studies funded by this grants program supported product approvals in 2016 alone, including much needed treatments for aortic wall injury in patients with coarctation of the aorta and severe hepatic veno-occlusive disease (also known as sinusoidal obstructive syndrome).

Good-Guy Bacteria May Help Cancer Immunotherapies Do Their Job

Individuals with certain types of bacteria in their gut may be more likely to respond well to cancer immunotherapy, researchers at the Harold C. Simmons Comprehensive Cancer Center found in a study of patients with metastatic melanoma.

The incidence of melanoma has been increasing over the past 40 years. Immunotherapies have dramatically improved the outlook for patients with metastatic melanoma in the past half-dozen years, but still only about half of these patients go into remission.

UT Southwestern cancer researchers analyzed the gut bacteria of 39 melanoma patients who were treated with immunotherapies and found a strong association between a good response and the presence of particular bacteria.

“Our research suggests there were certain good-guy bacteria that are needed to optimize the effectiveness of checkpoint inhibitors. These bacteria somehow prime your immune system so that it’s better able to attack cancer cells and kill them,” said senior author Dr. Andrew Koh, Associate Professor of Pediatrics and Microbiology with the Simmons Cancer Center.

Rick Spurr, former CEO of Zix, a company that provides email encryption services for banks and health care facilities, volunteered for the study that helped identify the link. The grandfather of six was diagnosed with metastatic melanoma, which was discovered on his lungs while he was fighting off a bout of pneumonia.

Mr. Spurr was treated with an every-other-week infusion of nivolumab, an immunotherapy drug that acts by lifting a brake on the immune system, allowing the body’s natural defenses to go into overdrive.

“I felt virtually no side effects from the treatment,” he said. “I started the treatment in the summer and I was skiing in November.”

Researchers found he had the beneficial gut bacteria and suspect this microbiome contributed to the outcome. As a group, patients who responded well to the immunotherapy had three specific bacteria:

  • Bacteroides thetaiotaomicron
  • Faecalibacterium prausnitzii
  • Holdemania filiformis

All three are common normal flora in the human intestinal tract.

After identifying the link, researchers looked for a potential reason for the association between the helper bacteria and immunotherapy effectiveness. “Is it something the bacteria are making? We examined metabolites in these subjects and found the strongest correlation between anacardic acid, present in cashews and mangoes, and the beneficial bacteria,” Dr. Koh said.

Researchers plan to follow up on the current research, which appears in the journal Neoplasia, with larger clinical studies.

“While these preliminary observations do not establish a firm causal connection between gut microbes and immunotherapy efficacy, they may lead eventually to a probiotic cocktail that could be given along with immunotherapy to enhance the chance of response,” said Dr. Koh, Director of Pediatric Hematopoietic Stem Cell Transplantation at UT Southwestern.

The research was supported by the Roberta I. and Norman L. Pollock Fund, the Melanoma Research Fund, the T. Boone Pickens Cancer Research Fund, the Cancer Prevention and Research Institute of Texas, and the National Institutes of Health.

The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 49 NCI-designated Comprehensive Cancer Centers in the nation. Simmons Cancer Center includes 13 major cancer care programs. In addition, the Center’s education and training programs support and develop the next generation of cancer researchers and clinicians. Simmons Cancer Center is among only 30 U.S. cancer research centers to be designated by the NCI as a National Clinical Trials Network Lead Academic Participating Site.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 100,000 hospitalized patients, 600,000 emergency room cases, and oversee approximately 2.2 million outpatient visits a year.

Drug combination may improve impact of immunotherapy in head and neck cancer

Checkpoint inhibitor-based immunotherapy has been shown to be very effective in recurrent and metastatic head and neck cancer but only in a minority of patients. University of California San Diego School of Medicine researchers may have found a way to double down on immunotherapy’s effectiveness.

In a paper published in the journal JCI Insights on September 21, researchers report that a combination of toll-like receptors (TLR) agonists — specialized proteins that initiate immune response to foreign pathogens or, in this case, cancer cells — and other immunotherapies injected directly into a tumor suppresses tumor growth throughout the whole body.

“The mechanism reverses the phenotype of a tumor by changing its inherit properties to make the tumor more immunogenic,” said Ezra E.W. Cohen, MD, professor of medicine at UC San Diego School of Medicine and associate director for translational science at UC San Diego Moores Cancer Center and senior author on the paper. “In this study, the combination of immunotherapy drugs resulted in the complete elimination of cancer cells and even when re-challenged the tumors did not recur.”

Macrophages are specialized immune cells that destroy targeted cells. They are supposed to present antigens to the immune system to get it started, but in cancer they stop doing that so the immune system is unable to recognize the cancer. The combination of drugs restored the ability of macrophages to initiate a tumor response and allow the immune system to eliminate the cancer.

To improve the efficiency of checkpoint inhibitor immunotherapy on human papillomavirus-negative and HPV-positive head and neck cancers, the team of researchers combined synthetic TLR7 and TLR9 that were developed by Dennis Carson, MD, Professor Emeritus at UC San Diego School of Medicine, with an inhibitor of the protein called programmed death-1 receptor (PD-1) which is responsible for turning off T cells.

TLR agonists cause an innate immune response — that is, the rapid response to a foreign substance in the body. This immediate protection comes at a cost since the nonspecific immune response may harm healthy cells if activation of the immune systems persists. PD-1 inhibitors stimulate an adaptive response calling on B cells and T cells to respond to a specific target, but this process takes longer to go into effect.

In mouse models, the combined TLR agonists and PD-1 inhibitors injected directly into a tumor incited a tumor-specific response by T cells which prevented metastasis or the spread of the cancer. When cancer had already spread, the TLR and anti-PD-1 combo eliminated the primary tumor as well as distant tumors. The combination therapy was more effective than either agent alone.

The next step should be to study these drugs in a clinical setting for head and neck cancer using FDA-approved immunotherapy. In addition, Cohen suggests studying these agents with other combinations such as chemotherapy and radiation therapy.

“As we make the tumor more immunogenic we should be making other therapies more effective and eliminate the cancer completely,” said Cohen.

MDI Biological Laboratory study finds immune system is critical to regeneration

The answer to regenerative medicine’s most compelling question — why some organisms can regenerate major body parts such as hearts and limbs while others, such as humans, cannot — may lie with the body’s innate immune system, according to a new study of heart regeneration in the axolotl, or Mexican salamander, an organism that takes the prize as nature’s champion of regeneration.

The study, which was conducted by James Godwin, Ph.D., of the MDI Biological Laboratory in Bar Harbor, Maine, found that the formation of new heart muscle tissue in the adult axolotl after an artificially induced heart attack is dependent on the presence of macrophages, a type of white blood cell. When macrophages were depleted, the salamanders formed permanent scar tissue that blocked regeneration.

The study has significant implications for human health. Since salamanders and humans have evolved from a common ancestor, it’s possible that the ability to regenerate is also built into our genetic code.

Godwin’s research demonstrates that scar formation plays a critical role in blocking the program for regeneration. “The scar shoots down the program for regeneration,” he said. “No macrophages means no cardiac regeneration.”

Godwin’s goal is to activate regeneration in humans through the use of drug therapies derived from macrophages that would promote scar-free healing directly, or those that would trigger the genetic programs controlling the formation of macrophages, which in turn could promote scar-free healing. His team is already looking at molecular targets for drug therapies to influence these genetic programs.

“If humans could get over the fibrosis hurdle in the same way that salamanders do, the system that blocks regeneration in humans could potentially be broken,” Godwin explained. “We don’t know yet if it’s only scarring that prevents regeneration or if other factors are involved. But if we’re really lucky, we might find that the suppression of scarring is sufficient in and of itself to unlock our endogenous ability to regenerate.”

The prevailing view in regenerative biology has been that the major obstacle to heart regeneration in mammals is insufficient proliferation of cardiomyocytes, or heart muscle cells. But Godwin found that cardiomyocyte proliferation is not the only driver of effective heart regeneration. His findings suggest that research efforts should pay more attention to the genetic signals controlling scarring.

The extraordinary incidence of disability and death from heart disease, which is the world’s biggest killer, is directly attributable to scarring. When a human experiences a heart attack, scar tissue forms at the site of the injury. While the scar limits further tissue damage in the short term, over time its stiffness interferes with the heart’s ability to pump, leading to disability and ultimately to terminal heart failure.

In addition to regenerating heart tissue following a heart attack, the ability to unlock dormant capabilities for regeneration through the suppression of scarring also has potential applications for the regeneration of tissues and organs lost to traumatic injury, surgery and other diseases, Godwin said.

Godwin’s findings are a validation of the MDI Biological Laboratory’s unique research approach, which is focused on studying regeneration in a diverse range of animal models with the goal of gaining insight into how to trigger dormant genetic pathways for regeneration in humans. In the past year and a half, laboratory scientists have discovered three drug candidates with the potential to activate regeneration in humans.

“Our focus on the study of animals with amazing capabilities for regenerating lost and damaged body parts has made us a global leader in the field of regenerative medicine,” said Kevin Strange, Ph.D., MDI Biological Laboratory president. “James Godwin’s discovery of the role of macrophages in heart regeneration demonstrates the value of this approach: we won’t be able to develop rational and effective therapies to enhance regeneration in humans until we first understand regeneration works in animals like salamanders.”

Godwin, who is an immunologist, originally chose to look at the function of the immune system in regeneration because its role as the equivalent of a first responder at the site of an injury means that it is responsible for preparing the ground for tissue repairs. The recent study was a follow-up to an earlier study which found that macrophages also play a critical role in limb regeneration.

The next step is to study the function of macrophages in salamanders and compare them with their human and mouse counterparts. Ultimately, Godwin would like to understand why macrophages produced by adult mice and humans don’t suppress scarring in the same way as in axolotls and then identify molecules and pathways that could be exploited for human therapies.

Godwin holds a dual appointment with The Jackson Laboratory, also located in Bar Harbor, which is focused on the mouse as a model animal. The dual appointment allows him to conduct experiments that compare genetic programming in the highly regenerative animals used as models at the MDI Biological Laboratory with genetic programming in neonatal and adult mice.

CRI Scientists Discover Vitamin C Regulates Stem Cell Function and Suppresses Leukemia Development

Not much is known about stem cell metabolism, but a new study from the Children’s Medical Center Research Institute at UT Southwestern (CRI) has found that stem cells take up unusually high levels of vitamin C, which then regulates their function and suppresses the development of leukemia.

“We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why. Our research provides part of the explanation, at least for the blood-forming system,” said Dr. Sean Morrison, the Director of CRI.

The metabolism of stem cells has historically been difficult to study because a large number of cells are required for metabolic analysis, while stem cells in each tissue of the body are rare. Techniques developed during the study, which was published in Nature, have allowed researchers to routinely measure metabolite levels in rare cell populations such as stem cells.

The techniques led researchers to discover that every type of blood-forming cell in the bone marrow had distinct metabolic signatures – taking up and using nutrients in their own individual way. One of the main metabolic features of stem cells is that they soak up unusually high levels of ascorbate. To determine if ascorbate is important for stem cell function, researchers used mice that lacked gulonolactone oxidase (Gulo) – a key enzyme that most mammals, including mice but not humans, use to synthesize their own ascorbate.

Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do. This gave CRI scientists strict control over ascorbate intake by the mice and allowed them to mimic ascorbate levels seen in approximately 5 percent of healthy humans. At these levels, researchers expected depletion of ascorbate might lead to loss of stem cell function but were surprised to find the opposite was true – stem cells actually gained function. However, this gain came at the cost of increased instances of leukemia.

“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said Dr. Michalis Agathocleous, lead author of the study, an Assistant Instructor at CRI, and a Royal Commission for the Exhibition of 1851 Research Fellow. “The epigenome is a set of mechanisms inside a cell that regulates which genes turn on and turn off.  So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.”

This increased risk is partly tied to how ascorbate affects an enzyme known as Tet2, the study showed. Mutations that inactivate Tet2 are an early step in the formation of leukemia. CRI scientists showed that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of leukemia.

These findings have implications for older patients with a common precancerous condition known as clonal hematopoiesis. This condition puts patients at a higher risk of developing leukemia and other diseases, but it is not well understood why certain patients with the condition develop leukemia and others do not. The findings in this study might offer an explanation.

“One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of Tet2. Our results suggest patients with clonal hematopoiesis and a Tet2 mutation should be particularly careful to get 100 percent of their daily vitamin C requirement,” Dr. Morrison said. “Because these patients only have one good copy of Tet2 left, they need to maximize the residual Tet2 tumor-suppressor activity to protect themselves from cancer.”

Researchers in the Hamon Laboratory for Stem Cell and Cancer Biology, in which Dr. Morrison is also appointed, intend to use the techniques developed as part of this study to find other metabolic pathways that control stem cell function and cancer development. They also plan to further explore the role of vitamin C in stem cell function and tissue regeneration.

Dr. Morrison is a Professor of Pediatrics at UT Southwestern, a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research, and a Howard Hughes Medical Institute (HHMI) Investigator. He also holds the Mary McDermott Cook Chair in Pediatric Genetics at UT Southwestern and the Kathryne and Gene Bishop Distinguished Chair in Pediatric Research at Children’s Research Institute at UT Southwestern.

CRI and UTSW co-authors include Dr. Zhiyu Zhao, Assistant Professor at CRI and of Pediatrics at UT Southwestern; Dr. Weina Chen, Associate Professor of Pathology at UT Southwestern; Dr. Corbin Meacham, Dr. Rebecca Burgess, and Dr. Malea Murphy, postdoctoral researchers; and Dr. Ralph DeBerardinis, Associate Professor at CRI, of Pediatrics, and in the Eugene McDermott Center for Human Growth & Development. Dr. DeBerardinis, who holds the Joel B. Steinberg, M.D. Chair in Pediatrics and is a Sowell Family Scholar in Medical Research at UTSW, also is the Director of CRI’s Genetic and Metabolic Disease Program and Chief of the Division of Pediatric Genetics and Metabolism at UTSW.

The National Institutes of Health, HHMI, CPRIT, and donors to the Children’s Medical Center Foundation supported this work.

Combination of Traditional Chemotherapy, New Drug Kills Rare Cancer Cells in Mice

An experimental drug combined with the traditional chemotherapy drug cisplatin, when used in mice, destroyed a rare form of salivary gland tumor and prevented a recurrence within 300 days, a University of Michigan study found.

Called adenoid cystic carcinoma, or ACC, this rare cancer affects 3,000-4,000 people annually, and typically arises in the salivary glands. It’s usually diagnosed at an advanced stage, is very resistant to therapy, and there’s no cure. People may have read about ACC in the news lately, because elite professional runner Gabe Grunewald is currently undergoing her fourth round of treatment since her 2009 ACC diagnosis.

Typically, oncologists treat ACC tumors with surgery and radiation. They rarely use chemotherapy because ACC is extremely slow-growing, and chemotherapy works best on cancers where cells divide rapidly and tumors grow quickly, said Jacques Nör, a U-M professor of dentistry, otolaryngology and biomedical engineering, and principal investigator on the study.

The Nör lab treated ACC tumors with a novel drug called MI-773, and then combined MI-773 with traditional chemotherapy cisplatin. MI-773 prevents a molecular interaction that causes tumor cells to thrive by disarming the critical cancer fighting protein, p53.

Study co-author Shaomeng Wang, U-M professor of medicine, pharmacology and medicinal chemistry, discovered MI-773, which is currently licensed to Sanofi.

Researchers believe that blocking that interaction sensitized ACC cancer cells to cisplatin––a drug that under normal conditions, wouldn’t work. When administered to the mice with ACC tumors, the cisplatin targeted and killed the bulk cells that form the tumor mass, while MI-773 killed the more resistant cancer stem cells that cause tumor recurrence and metastasis.

“This drug MI-773 prevents that interaction, so p53 can induce cell death,” Nör said.  “In this study, when researchers activated p53 in mice with salivary gland cancer, the cancer stem cells died.”

The key is that in many other types of cancer, p53 is mutated so it can’t kill cancer cells, and this mutation renders the MI-773 largely ineffective. However, in most ACC tumors p53 is normal, and Nör said researchers believe this makes these tumors good candidates for this combined therapy.

Researchers performed two different types of experiments to test ACC tumor reduction and recurrence. First, they treated tumors in mice with a combination of MI-773 and cisplatin, and tumors shrank from about the size of an acorn to nearly zero.

In the second experiment, the acorn-sized tumors were surgically removed, and for one month the mice were treated with MI-773 only, with the hope of eliminating the cancer stem cells that fuel recurrence and metastasis.

“We did not observe any recurrence in the mice that were treated with this drug after 300 days (about half of mouse life expectancy), and we observed about 62 percent recurrence in the control group that had only the surgery,” Nör said. “It’s our belief that by combining conventional chemotherapy with MI-773, a drug that kills more cancer stem cells, we can have a more effective surgery or ablation.”

One limitation of the study is that it’s known that about half of all ACC tumors recur only after about 10 years, and this observational period was only 300 days.

In a typical metastasis, the cancer cells spread through the blood to other parts of the body. But ACC cancer cells like to move by “crawling” along nerves, and it’s common for ACC tumor cells to follow the prominent facial nerves to the brain––picture a mountain climber ascending a rope––where it’s often fatal.

Research is still too early-stage to know how humans will respond, and the drug will work primarily in tumors where p53 is normal. If p53 is mutated, which is fairly common in other tumor types, this drug won’t work as well, Nör said.

The work was funded by the Adenoid Cystic Carcinoma Research Foundation, U-M and the National Institutes of Health.

The study, “Therapeutic Inhibition of the MDM2-p53 interaction prevents recurrence of adenoid cystic carcinomas,” appeared earlier this year in the journal Clinical Cancer Research.

Prostate Cancer Cells Become ‘Shapeshifters’ to Spread to Distant Organs

Johns Hopkins Kimmel Cancer Center scientists report they have discovered a biochemical process that gives prostate cancer cells the almost unnatural ability to change their shape, squeeze into other organs and take root in other parts of the body. The scientists say their cell culture and mouse studies of the process, which involves a cancer-related protein called AIM1, suggest potential ways to intercept or reverse the ability of cancers to metastasize, or spread.

Results of the research are described in the July 26 issue of Nature Communications.

For the study, the Johns Hopkins scientists mined publically available research data on the genetics and chemistry of hundreds of primary and metastatic cancers included in five studies of men with prostate cancer. They found that a gene called AIM1 (aka “absent in melanoma 1”), which makes proteins also called AIM1, is deleted in approximately 20 – 30 percent of prostate cancers confined to the gland and about 40 percent of metastatic prostate cancers. In addition, the scientists found, on average, two- to fourfold less amounts of AIM1 expression in metastatic prostate cancers compared with normal prostate cells or those from men with prostate cancers confined to the prostate, suggesting that reduction of AIM1 proteins is somehow linked to tumor spread.

Aside from its link to the development of melanoma, a deadly skin cancer, scientists knew little about the function of AIM1.

“Our experiments show that loss of AIM1 proteins gives prostate cancer cells the ability to change shape, migrate and invade. These abilities could allow prostate cancer cells to spread to different tissues in an animal and presumably a person,” says Michael Haffner, M.D., Ph.D., a pathology resident and former postdoctoral fellow at the Johns Hopkins Kimmel Cancer Center who is involved in the research. “It’s not the whole story of what is going on in the spread of prostate cancer, but it appears to be a significant part of it in some cases.”

Looking more closely at the AIM1 gene and its protein levels in prostate cancer tissues, the Johns Hopkins scientists found that many times, even when the gene isn’t completely deleted and its protein production is reduced, its location in the prostate cancer cell is highly abnormal compared with normal prostate cells. This occurs even in primary prostate cancer cells, which have invaded the local structures to form invasive cancer within the prostate gland, say the scientists.

The research team used dyes to track the location of AIM1 proteins in human cells grown in the lab and followed where they appear in normal and cancerous prostate tissues. In normal prostate cells, AIM1 was located along the outside border of each cell and paired up with a protein called beta-actin that helps form the cell’s cytoskeleton, or scaffolding. However, in prostate cancer cells, the protein spread away from the outer border of the cells and no longer paired up with beta-actin.

The scientists found this pattern among a set of human prostate tissue samples including 81 normal prostates, 87 localized prostate cancers and 52 prostate cancers that had spread to the lymph nodes.

“It appears that when AIM1 protein levels drop, or when it’s abnormally spread throughout the cell instead of confined to the outer border, the prostate cancer cells’ scaffolding becomes more malleable and capable of invading other tissues,” says Vasan Yegnasubramanian, M.D., Ph.D., associate professor at the Kimmel Cancer Center and a member of the research team. With AIM1, the scaffold, Yegnasubramanian says, keeps normal cells in a rigid, orderly structure. Without AIM1, cells become more malleable, shapeshifting nomads that can migrate to other parts of the body, he says.

To track how these shapeshifting cancer cells move, the Johns Hopkins scientists, with Steven An, Ph.D., an expert in cellular mechanics and an associate professor at the Johns Hopkins Bloomberg School of Public Health, took a close-up look at AIM1-lacking prostate cancer cells, using sophisticated and quantitative single-cell analyses designed to probe the material and physical properties of the living cell and its cytoskeleton.

They found that cells lacking AIM1 remodeled their scaffolding more than twice as much as cells that had normal levels of AIM1, and that they exert three- to fourfold more force on their surroundings than cells with normal levels of the protein. Such cellular properties are reminiscent of cells with high potential to invade and migrate, An notes.

In addition, the scientists found that AIM1-lacking prostate cells were capable of migrating to unoccupied spaces on a culture dish or invading through connective tissue-like materials at rates fourfold higher than cells with normal levels of AIM1.

Next, the scientific team implanted human prostate cancer cells engineered without AIM1 in five mice and found that the cells spread to other tissues at levels 10 to 100 times more than cells with normal levels of AIM1 that were implanted in five similar mice. However, the AIM1-lacking cells were not able to establish full colonies and tumors at those other tissues, suggesting that AIM1 depletion is not the whole story in the spread and growth of metastatic prostate cancer.

“AIM1 may help prostate cancer cells disseminate throughout the body, but something else may be helping them form full-blown metastatic tumors when they get there,” says Yegnasubramanian.

The Johns Hopkins scientists plan to further study what happens to the AIM1 protein to cause its abnormal location in prostate cancers and identify other proteins and genes that work with AIM1 to cause metastasis. Such studies could help scientists find new drug targets aimed at preventing or reversing prostate metastasis.

New Therapeutic Approach for Difficult-to-Treat Subtype of Ovarian Cancer Identified

Scientists from The Wistar Institute demonstrate how a mutation in ovarian clear cell carcinoma can be exploited to design a targeted treatment.

A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Ovarian clear cell carcinoma accounts for approximately 5 to 10 percent of American ovarian cancer cases and about 20 percent of cases in Asia, ranking second as the cause of death from ovarian cancer. People with the clear cell subtype typically do not respond well to platinum-based chemotherapy, leaving limited therapeutic options for these patients.

Previous studies, including those conducted at The Wistar Institute, have revealed the role of ARID1A, a chromatin remodeling protein, in this ovarian cancer subtype. When functioning normally, ARID1A regulates expression of certain genes by altering the structure of chromatin – the complex of DNA and proteins in which DNA is packaged in our cells. This process dictates some of our cells’ behaviors and prevents them from becoming cancerous.

“Conventional chemotherapy treatments have proven an ineffective means of treating this group of ovarian cancer patients, meaning that alternative strategies based on a person’s genetic makeup must be explored,” said Rugang Zhang, Ph.D., professor and co-program leader in Wistar’s Gene Expression and Regulation Program and corresponding author of the study. “Therapeutic approaches based on the ARID1A mutation have the potential to revolutionize the way we treat these patients.”

Recent studies have shown that ARID1A is mutated in more than 50 percent of cases of ovarian clear cell carcinoma. Mutations of ARID1A and the tumor suppressor gene TP53 are mutually exclusive, meaning that patients with a mutation of ARID1A do not also carry a mutation of TP53. Despite this, the function of TP53, which protects the integrity of our genome and promotes programmed cell death, is clearly impaired as patients with the disease still have a poor prognosis.

In this study, Zhang and colleagues studied the connection between ARID1A and histone deacetylases (HDACs), a group of enzymes involved in key biological functions. They found that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. They were able to show that HDAC6 is typically inhibited by ARID1A, whereas in the presence of mutated ARID1A, HDAC6 levels increase. Because HDAC6 suppresses the activity of TP53, therefore inhibiting its tumor suppressive functions, higher level of HDAC6 allow the tumor to grow and spread.

Using a small molecule drug called rocilinostat that selectively inhibits HDAC6, the Zhang lab found that by blocking the activity of the enzyme in ARID1A-mutated cancers, they were able to increase apoptosis, or programmed cell death, in only those tumor cells containing the ARID1A mutation. This correlated with a significant reduction in tumor growth, suppression of peritoneal dissemination and extension of survival of animal models carrying ARID1A-mutated ovarian tumors.

“We demonstrated that targeting HDAC6 activity using a selective inhibitor like rocilinostat represents a possible therapeutic strategy for treating ovarian clear cell carcinoma and other tumors impacted by mutated ARID1A,” said Shuai Wu, Ph.D., a postdoctoral fellow in the Zhang lab and co-first author of the study. “Inhibitors like the one we used in this study have been well-tolerated in clinical trials, so our findings may have far-reaching applications.”

Childhood obesity major link to hip diseases

New research from the University of Liverpool, published in the Archives of Disease in Childhood journal, shows a strong link between childhood obesity and hip diseases in childhood.

Significant hip deformities affect around 1 in 500 children. Slipped Capital Femoral Epiphysis (SCFE) is the most common hip disease of adolescence. The condition always requires surgery, can cause significant pain, and often leads to a hip replacement in adolescence or early adulthood.

Children with a SCFE experience a decrease in their range of motion, and are often unable to complete hip flexion or fully rotate the hip inward. Unfortunately many cases of SCFE are misdiagnosed or overlooked, because the first symptom is knee pain, referred from the hip. The knee is often investigated and found to be normal. Early recognition of SCFE is important as the deformity may worsen if the slip remains untreated.

Factors explored

In an effort to identify children at higher risk of this condition researchers from the University’s Institute of Translational Medicine, led by National Institute of Health Research (NIHR) Clinician Scientist and Senior Lecturer in Orthopaedic Surgery Daniel Perry, examined hospital and community based records to explore factors associated with SCFE, and explanations for diagnostic delays.

All of the records examined were of individuals under 16-years-of-age with a diagnosis of SCFE and whose electronic medical record was held by one of 650 primary care practices in the UK between 1990 and 2013.

Using the height and weight of children recorded in the notes at some point before the disease was diagnosed the researchers were able to identify that obese children appear at highest risk of this condition.

The study was funded by the Academy of Medical Sciences.

Best evidence

Daniel Perry, who is also an Honorary Consultant Orthopaedic Surgeon at Alder Hey Children’s Hospital, said: “This is the best evidence available linking this disease to childhood obesity – which makes this condition to be one of the only obesity-related disease that can cause life-long morbidity starting in childhood.

“A significant proportion of patients with SCFE are initially misdiagnosed and those presenting with knee pain are particularly at risk.

“Ultimately this study helps us to better understand one of the main diseases affecting the hip in childhood. Whilst we confirm a strong association with obesity, we are still unable to say that obesity causes this disease.”

Researchers Studying Debilitating Lung Disease that Targets Puerto Ricans

Loyola Medicine is enrolling patients in the first major study of a rare, debilitating lung disease that disproportionately affects people from Puerto Rico.

The hereditary disease is called Hermansky-Pudlak syndrome (HPS). It can cause bleeding problems, low vision, albinism and in some patients, a debilitating and often fatal lung disease called pulmonary fibrosis, said Loyola Medicine pulmonologist Daniel Dilling, MD.

HPS affects fewer than 1 in 500,000 people worldwide. But it is more common in certain geographic pockets, especially Puerto Rico, where it affects 1 in 1,800 people.

Loyola is the only center in Illinois participating in a multicenter study of how HPS develops in patients over time. The first Loyola HPS patient to enroll is Jonathan Colon, 44, of Chicago, whose parents are from Puerto Rico. Puerto Ricans who have HPS are believed to have descended from a single founding patient.

Mr. Colon has pulmonary fibrosis, characterized by a buildup of scar tissue in the lungs. Pulmonary fibrosis makes breathing increasingly difficult, and in later stages patients need supplemental oxygen around the clock. Small exertions such as walking across a room can leave a patient gasping for breath. Without a lung transplant, the condition can be fatal.

The course of the disease varies among patients. Mr. Colon was diagnosed relatively early in the disease, and is taking a new drug that has slowed the progression of his pulmonary fibrosis. Dr. Dilling said Mr. Colon eventually may need a lung transplant. The operation would be challenging, because in HPS patients, blood does not coagulate normally, increasing the risk of bleeding.

Dr. Dilling said people of Puerto Rican descent who have albinism (abnormally light coloring) should be screened for HPS to ensure early treatment. Many Puerto Ricans with albinism do not know they are at risk for HPS, Dr. Dilling said.

The study is called “A Longitudinal Study of Hermansky-Pudlak Syndrome Pulmonary Fibrosis.” Its purpose is to identify the earliest evidence of pulmonary disease in individuals who are at risk for HPS pulmonary fibrosis. Researchers also hope to identify biomarkers that will help them understand the cause of HPS pulmonary fibrosis and facilitate future clinical trials. (A  biomarker is a substance in the body that predicts the incidence or outcome of a disease.)

The study is funded by the National Heart, Lung and Blood Institute of the National Institutes of Health. Principal investigator of the overall study is Lisa Young, MD, of Vanderbilt University.

For 29 years, Loyola has operated the largest and most successful lung transplant program in Illinois. More than 900 lung transplants—by far the most of any center in Illinois—have been performed and Loyola’s 40 lung transplants in 2016 were more than all other programs in Illinois combined.

Loyola’s lung transplant program regularly evaluates and successfully performs transplants in patients who have been turned down by other centers in Chicago and surrounding states and consistently records outstanding outcomes.

Loyola also is the only center in Illinois to join the recently launched Rare Lung Diseases Consortium, which is spearheading cutting-edge research on HPS and other rare lung diseases.The consortium is a unique collaboration among patient groups, researchers and the National Institutes of Health. Its mission is to conduct research into new diagnostic tests and treatments, provide clinical research training and focused clinical care and educate patients, physicians, researchers and the public about rare lung diseases.

The study will enroll about 150 patients aged 12 and older who have been diagnosed with HPS. For more information about enrolling at the Loyola site, contact Josie Corral, RN, at 708-216-5744 or at  jcorral@luc.edu.

First Large-Scale Genomic Analysis of Key Acute Leukemia Will Likely Yield New Therapies

A consortium including St. Jude Children’s Research Hospital and the Children’s Oncology Group has performed an unprecedented genomic sequencing analysis of hundreds of patients with T-lineage acute lymphoblastic leukemia (T-ALL). The results provide a detailed genomic landscape that will inform treatment strategies and aid efforts to develop drugs to target newly discovered mutations.

The data will also enable researchers to engineer better mouse models to probe the leukemia’s aberrant biological machinery.

The project’s 39 researchers were led by Charles Mullighan, M.D., MBBS, a member of the St. Jude Department of Pathology, with co-corresponding authors Jinghui Zhang, Ph.D., chair of the St. Jude Department of Computational Biology and Stephen Hunger, M.D., of the Children’s Hospital of Philadelphia. The research was selected for advance online publication today in the journal Nature Genetics.

“This first comprehensive and systematic analysis in a large group of patients revealed many new mutations that are biologically significant as well as new drug targets that could be clinically important,” Mullighan said. “Leukemias typically arise from multiple genetic changes that work together. Most previous studies have not had the breadth of genomic data in enough patients to identify the constellations of mutations and recognize their associations.”

T-ALL is a form of leukemia in which the immune system’s T cells acquire multiple mutations that freeze the cells in an immature stage, causing them to accumulate in the body. ALL is the most common type of childhood cancer, affecting about 3,000 children nationwide each year. T-ALL constitutes about 15 percent of those cases. While about 90 percent of children with ALL can be cured, many still relapse and require additional treatment.

The multi-institutional effort involved sequencing the genomes of 264 children and young adults with T-ALL—the largest such group ever analyzed. The study involved sophisticated analysis of multiple types of genomic data, led by Yu Liu, Ph.D., a postdoctoral fellow in Zhang’s Computational Biology laboratory and first author of the study. Their analyses identified 106 driver genes—those whose mutations trigger the malfunctions that block normal T cell development and give rise to cancer. Half of those mutated genes had not been previously identified in childhood T-ALL.

The study enabled the researchers to compare the frequencies of mutations among patients whose cancerous cells were sequenced at the same detailed level, Mullighan said. Also important, he said, was that all the patients had uniform treatment, which enabled the researchers to draw meaningful associations between the genetics of their cancer and the response to different treatments. Such associations will enable better diagnosis and treatment of T-ALL with existing drugs.

Researchers analyzed the cancerous T cells as well as those that treatments had rendered non-cancerous. Comparing the two populations of cells could reveal valuable clues about why specific treatments were successful in thwarting particular cancer-causing mutations.

The findings revealed significant unexpected findings. “We went into this study knowing that we didn’t know the full genomic landscape of T-ALL,” Hunger said. “But we were surprised that over half of the new targets and mutations were previously unrecognized. It was particularly unexpected and very striking that some mutations were exclusively found in some subtypes of T-ALL, but not others.”

Cancers are driven by mutations in genes that are the blueprint for protein enzymes in signaling pathways in cells—the biological equivalent of circuits in a computer. While a cancer may arise from an initial founding mutation, that mutation triggers a cascade of other mutations that help drive the cancer.

The new genomic analysis confirmed that T-ALL was driven by mutations in known signaling pathways, including JAK–STAT, Ras and PTEN–PI3K.

However, the new analysis identified many more genetic mutations in those known pathways. The findings offered more targets for drugs to shut down the aberrant cells. “So the frequency of the patients that are potentially amenable to these targeted approaches is higher than we appreciated before,” Mullighan said.

The researchers also found cases in which the same T-ALL subtype had mutations in different pathways triggered by the same cancer-causing founding mutation. “We believe this finding suggests we can target such subtypes with an inhibitor drug for one of the pathways, and it’s likely to be effective,” Mullighan said.

The multitude of new mutations uncovered in the new study will also enable researchers to use genetic engineering to create mouse models that more accurately reflect human cancer, he said. Such models are invaluable for understanding the biological machinery of T-ALL, as well as testing new drug strategies. “We now have a launching pad, if you will, to design mouse models that include multiple genetic mutations to more faithfully reflect the leukemias we see in humans,” Mullighan said.

The research also offers a broader lesson for genomic studies of cancers, Zhang said. “Our study is further evidence that if you systematically study a large enough population with careful, detailed genomic analysis, you will discover new mutational patterns of collaboration or exclusion across multiple genes unique to each T-ALL subtype,” she said.

The study was a collaboration between the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project, the Children’s Oncology Group (COG) and the National Cancer Institute’s Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. COG is a federally supported clinical trials group focused exclusively on childhood cancer. TARGET uses genomic analysis of COG samples to identify therapeutic targets and spur development of more effective treatment for childhood cancer.

Research could give insight into genetic basis of of the human muscle disease, myopathy

Pioneering research using the tropical zebrafish could provide new insights into the genetic basis of myopathy, a type of human muscle disease.

An international research team, led by Professor Philip Ingham FRS, inaugural Director of the University of Exeter’s Living Systems Institute — has taken the first steps in determining the central role a specific gene mutation in a poorly characterised human myopathy.

Myopathies are diseases that prevent muscle fibres from functioning properly, causing muscular weakness. At present, there is no single treatment for the disease, as it can develop via a number of different pathways.

One particular type is nemaline myopathy, which primarily affects skeletal muscles and can lead to sufferers experiencing severe feeding and swallowing difficulties as well as limited locomotor activity.

Mutations in a specific gene, called MY018B, have recently been found to be present in people exhibiting symptoms of this disease, but the role these mutations play in muscle fibre integrity has until now been unclear.

In this new research, the Ingham team, based in Singapore and Exeter, has used high-resolution genetic analysis to create a zebrafish model of MYO18B malfunction; this research takes advantage of the remarkable similarity between the genomes of zebrafish and humans, — which have more than 70 per cent of their genes in common.

The Singapore/Exeter team found that the MYO18B gene is active specifically in the ‘fast-twitch’ skeletal muscles of the zebrafish, typically used for powerful bursts of movement. Crucially, by studying fish in which the MYO18B gene is disrupted, they were able to show that it plays an essential role in the assembly of the bundles of actin and myosin filaments that give muscle fibres their contractile properties.

The team believe this new research offers a vital new step towards understanding the cause of myopathy in humans, which in turn could give rise to new, tailored treatments in the future.

The leading research is published in the scientific journal, Genetics.

Professor Ingham, said: “The identification of a MYO18B mutation in zebrafish provides the first direct evidence for its role in human myopathy and gives us a model in which to study the molecular basis of MYO18B function in muscle fibre integrity.”

A pioneer in the genetic analysis of development using fruit flies and zebrafish as model systems, Prof Ingham is internationally renowned for his contributions to several influential discoveries in the field of developmental biology over the last century.

This is the latest research by Professor Ingham that has revealed important links between the processes that underpin normal embryonic development and disease.

His co-discovery of the ‘Sonic Hedgehog’ gene, recognised as one of 24 centennial milestones in the field of developmental biology by Nature, in 2004, led directly to the establishment of a biotechnology company that helped develop the first drug to target non-melanoma skin cancer.

The research comes at the University of Exeter holds the official opening of the Living Systems Institute with an Opening Symposium event, from July 5-6 2017.

Two Nobel Laureates, Sir Paul Nurse FRS and Christiane Nüsslein-Volhard ForMemRS, who separately won the Nobel Prize for Physiology or Medicine, will deliver keynote speeches as part of the opening event.

The high-profile event, held at the University’s Streatham Campus marks the official opening of the LSI — a £52 million inter-disciplinary research facility designed to bring new, crucial insights into the causes and preventions of some of the most serious diseases facing humanity.

A Zebrafish Model for a Human Myopathy Associated with Mutation of the Unconventional Myosin MYO18B is published in Genetics.

HPV Testing Leads to Earlier Detection and Treatment of Cervical Precancer

Women who receive human papillomavirus (HPV) testing, in addition to a pap smear, receive a faster, more complete diagnosis of possible cervical precancer, according to a study of over 450,000 women by Queen Mary University of London (QMUL) and the University of New Mexico (UNM) Comprehensive Cancer Center.

HPV is a virus that can cause cervical, vaginal, penile and anal cancers. More than 520,000 cases of cervical cancer are diagnosed worldwide each year, causing around 266,000 deaths. A common screening procedure for cervical cancer is the Pap smear, which tests for the presence of precancerous or cancerous cells on the cervix.

The study, published in JAMA Oncology, used data from the New Mexico HPV Pap Registry in the United States. It is the first comprehensive evaluation of HPV testing on the long-term outcomes of women who had received a borderline abnormal Pap test result.

A total of 457,317 women were included in the study. Of these, 20,677 women (4.5 percent) received a borderline abnormal result through a Pap smear and were followed in the study for five years. Some of the women with borderline abnormal Pap smear results had an HPV test.

HPV testing led to a 15.8 percent overall increase in the detection of cervical precancers and time to detection was much shorter (a median of 103 days versus 393 days).

Virtually all cervical pre-cancers were detected in women who tested positive for HPV, suggesting HPV testing to be a good additional screening method after the Pap smear. Colposcopy, which is a medical examination of the cervix, could then be focused on women who would need it most: those with a positive HPV test.

At the same time, however, HPV testing of women resulted in 56 percent more biopsies and a 20 percent increase in surgical treatment procedures performed. Most of the additional biopsies were for low grade lesions which could have regressed, indicating some overtreatment due to HPV testing.

Professor Jack Cuzick from QMUL said: “This study shows that knowing a woman’s HPV status can help determine her likelihood of needing additional procedures, and prioritise immediate treatment and medical resources to the women who need them most.”

Professor Cosette Wheeler from the UNM Comprehensive Cancer Center said: “The benefits of HPV testing outweigh the harms observed but it’s important to understand and quantify the harms as well.”

The authors warn that, as this was an observational study, the use of HPV testing was not randomised. So, it is also possible that there could be socioeconomic or other relevant differences among health care facilities that have not been measured.

New inhibitor drug shows promise in relapsed leukemia

A new drug shows promise in its ability to target one of the most common and sinister mutations of acute myeloid leukemia (AML), according to researchers at the Perelman School of Medicine at the University of Pennsylvania and Penn’s Abramson Cancer Center. The Fms-like tyrosine kinase 3 (FLT3) gene mutation is a known predictor of AML relapse and is associated with short survival. In a first-in-human study, researchers treated relapsed patients with gilteritinib, an FLT3 inhibitor, and found it was a well-tolerated drug that led to frequent and more-sustained-than-expected clinical responses, almost exclusively in patients with this mutation. They published their findings today in The Lancet Oncology.

FLT3 is one of the most commonly mutated genes in AML patients. FLT3 mutations are found in about 30 percent of patients’ leukemia cells. Clinically, these mutations are associated with aggressive disease that often leads to rapid relapse, after which the overall survival is an average of about four months with current therapies. To avoid relapse, oncologists often recommend the most aggressive chemotherapy approaches for patients with FLT3 internal tandem duplication (FLT3-ITD), including marrow transplantation. But even that cannot always stave off the disease.

The FLT3 gene is present in normal bone marrow cells and regulates the orderly growth of blood cells in response to daily demands. When the gene is mutated in a leukemia cell, however, the mutated cells grow in an uncontrolled manner unless the function of FLT3 is turned off.

“Other drugs have tried to target these mutations, and while the approach works very well in the laboratory, it has proven very challenging to develop FLT3 inhibitors in the clinic for several reasons,” said Alexander Perl, MD, MS, an assistant professor of Hematology Oncology in Penn’s Abramson Cancer Center and the study’s lead author. “First, we’ve learned it takes unusually potent inhibition of the FLT3 target to generate clinical responses. Second, many of these drugs are not selective in their activity against FLT3. When they target multiple kinases, it can lead to more side-effects. That limits whether you can treat a patient with enough drug to inhibit FLT3 at all. Finally, with some FLT3 inhibitors, the leukemia adapts quickly after response and cells can develop new mutations in FLT3 that don’t respond to the drugs at all. So ideally, you want a very potent, very selective, and very smartly designed drug. That’s hard to do.”

For this phase 1/2 clinical trial, Perl and his team evaluated the drug gilteritinib – also known as ASP2215 – at increasing doses in patients whose AML had relapsed or was no longer responding to chemotherapy. The team focused on dose levels at 80mg and above, which were associated with more potent inhibition of the FLT3 mutation and higher response rates. They found these doses were also associated with longer survival. Of the 252 patients on this study, 67 were on a 120mg dose and 100 were on a 200mg dose. Seventy-six percent (191) of the patients on the trial had a FLT3 mutation. Overall, 49 percent of patients with FLT3 mutations showed a response. Just 12 percent of patients who didn’t have the mutation responded to the drug.

“The fact that the response rate tracked with the degree of FLT3 inhibition and was so much lower among patients who did not have an FLT3 mutation gives us confidence that this drug is hitting its target,” Perl said.

In leukemia cells, FLT3 itself can mutate again to a form called a D835 mutation that is resistant to several FLT3 inhibitors treatments. Gilteritinib, however, remains active against D835 mutations in laboratory models of leukemia. Clinical response rates from the trial appeared to be the same, whether patients had a FLT3-ITD alone or both a FLT3-ITD and a D835 mutation. The response rates also were similar in patients in whom gilteritinib was their first FLT3 inhibitor and those who previously were treated with other FLT3 inhibitors.

The drug was also generally well-tolerated. The three most common side effects attributed to the drug were diarrhea in 41 patients (16 percent), fatigue in 37 (15 percent), and abnormal liver enzyme tests in 33 (13 percent). These generally were mild in severity and discontinuation of gilteritinib for side effects was uncommon (25 patients, 10 percent).

“These look like data you want to see for a drug to eventually become a standard therapy,” Perl said, though he noted more research will be necessary.

A new multicenter trial, which compares gilteritinib to standard chemotherapy in patients with FLT3 mutations who relapsed or did not respond to initial therapy, is now underway, and Penn’s Abramson Cancer Center is one of the sites.

There are also studies underway that give the drug in combination with frontline chemotherapy and as an adjunct to bone marrow transplantation in hopes of preventing relapse altogether.

Penn study details impact of antibiotics, antiseptics on skin microbiomes

The use of topical antibiotics can dramatically alter communities of bacteria that live on the skin, while the use of antiseptics has a much smaller, less durable impact. The study, conducted in mice in the laboratory of Elizabeth Grice, PhD, an assistant professor of Dermatology in the Perelman School of Medicine at the University of Pennsylvania, is the first to show the long-term effects of antimicrobial drugs on the skin microbiome. Researchers published their findings today in the journal Antimicrobial Agents and Chemotherapy.

The skin, much like the gut, is colonized by a diverse multitude of microorganisms which generally coexist as a stable ecosystem — many of which are harmless or even beneficial to the host. However, when that ecosystem is disturbed or destabilized, colonization and/or infection by more dangerous microbes can occur. Antiseptics, such as ethanol or iodine, are commonly used to disinfect the skin prior to surgical procedures or following exposure to contaminated surfaces or objects. Topical antibiotics may be used to decolonize skin of specific types of bacteria or for rashes, wounds, or other common conditions.

In the gut, research shows medication that alters microbial communities can lead to complications like Clostridium difficile, or C. diff — which causes diarrhea and is the most common hospital-acquired infection. But when it comes to the skin, the impact of these medications on bacteria strains like Staphylococcus aureus, or S. aureus — the most common cause of skin infections — is still largely unstudied.

“We know antibiotics and antiseptics can be effective in stopping the growth of certain bacteria, but we wanted to know about the larger impact these treatments can have on the resident microbial communities on the skin,” said the study’s lead author, Adam J. SanMiguel, PhD, a researcher in the Grice Laboratory at Penn.

Researchers treated the skin of hairless mice with a variety of antibiotics, including a narrowly targeted mupirocin ointment and a broadly applicable triple-antibiotic ointment (TAO) containing bacitracin, neomycin, and polymyxin B. All of the antibiotics changed the makeup of the microbial communities, and, in a key finding of the study, the impact of that change lasted for days after treatment stopped.

“The problem in this case isn’t antibiotic resistance, but instead, how long the disruption of the skin microbiomes continues,” SanMiguel said. “That disruption opens the door for colonization by an unwanted strain.”

The researchers similarly evaluated antiseptics, using alcohol or povidone-iodine and comparing those treatments with two control groups – mice treated with water and mice entirely untreated. They found neither antiseptic caused responses similar enough to cluster the mice together into groups based on their microbiomes. They also found no clear difference between the treatment groups and the control groups when comparing the relative number of individual bacteria strains.

“We thought antiseptics would be even more disruptive to microbial communities than antibiotics since they are less targeted, but it turns out the opposite is true,” SanMiguel said. “It shows how stable the skin microbiome can be in the face of stress.”

However, both antibiotic and antiseptic treatments removed skin resident bacteria that compete against the pathogenic S. aureus to colonize the skin. Colonization with S. aureus is a risk factor for developing a skin infection.

“This gives us a better understanding of how topical antimicrobials affect the skin microbiome and what kind of impact their disturbance can have in the context of pathogenic colonization,” said Grice, the study’s senior author. “This helps us anticipate their potential effects.”

The researchers say this work can provide the foundation for greater understanding of how the skin defends against infection. They have already begun similar testing in humans.