HIV Uses Immune System’s Own Tools to Suppress Itself

Canadian scientists make a significant discovery on HIV persistence

A Canadian research team at the IRCM in Montr?al, led by molecular virologist ?ric A. Cohen, PhD, made a significant discovery on how HIV escapes the body’s antiviral responses. The team uncovered how an HIV viral protein known as Vpu tricks the immune system by using its own regulatory process to evade the host’s first line of defense.?The findings pave the way for future HIV prevention or cure strategies.

The study’s goal was to determine how HIV manages to compromise antiviral responses in the initial period of infection, also called the acute infection stage, during which the virus establishes itself in the body. The acute infection is considered a critical period in determining the complexity, extent and progression of the disease. It is also during this stage that HIV establishes latent infection in long-lasting cellular reservoirs. These viral reservoirs, which harbor the virus out of sight from the immune system and antiviral drugs, represent the primary barrier to a cure.

“An important component in this process is a group of proteins collectively called type 1 Interferons, which are the immune system’s first line of defense against viral infections and are known to have a beneficial role in the early stages of HIV infection,” says Dr. Cohen, Director of the Human Retrovirology research unit at the IRCM. “The problem is that HIV has developed mechanisms to suppress the Interferon response and, until now, little was known about how this was achieved.”

PHIL-18143 PubDomLic SEM HIV Particles courtesy NIAID
SEM HIV Particles courtesy NIAID PHIL-18143

Most of the Interferon is produced by a very small population of immune cells called pDCs (plasmacytoid dendritic cells), responsible for providing immediate defense against infections. PDCs patrol the body to detect invaders and, when they recognize the presence of a pathogen, they secrete Interferon. The Interferon then triggers a large array of defense mechanisms in nearby cells, creating an antiviral state that prevents the dissemination and, ultimately, the expansion of the virus.

“When pDCs encounter HIV-infected cells, the production of Interferon is regulated by a protein located on the infected cell’s surface called BST2,” explains Mariana Bego, PhD, first author of the study and research associate in Dr. Cohen’s laboratory. “BST2 has the ability to bind to and activate a receptor called ILT7, found on the surface of pDCs, which, in turns, sends a signal that suppresses the production of Interferon and halts its defensive functions. Interestingly, BST2 is also responsible for restricting HIV production by trapping the virus at the cell surface before it can exit infected cells and disseminate. However, HIV uses the viral protein Vpu to counteract BST2 antiviral activity.”

“With this study, we uncovered a unique mechanism whereby HIV exploits the regulatory process between BST2 and ILT7 to limit the body’s antiviral response, which allows the virus to spread and leads to persistent infection,” adds Dr. Bego. “We found that HIV, through Vpu, takes advantage of the role played by BST2 by maintaining its ability to activate ILT7 and limit the production of Interferon, all the while counteracting its direct antiviral activity on HIV production.”

“The hope for a definitive cure and an effective vaccine has been frustrated by HIV’s endless propensity to subvert the host’s defenses and persist in small populations of long-lasting reservoirs despite antiretroviral therapy,” describes Dr. Cohen, who also leads CanCURE, a team of leading Canadian researchers working towards an HIV cure. “Our findings can provide tools to enhance antiviral responses during the early stages of infection. By blocking Vpu’s action, we could prevent early viral expansion and dissemination, while also allowing pDCs to trigger effective antiviral responses. We believe that such interventions during primary infection have the potential to limit the establishment and complexity of viral reservoirs, a condition that seems required to achieve a sustained HIV remission.”

“The discovery by Drs. Bego and Cohen, which explains how the virus can’t be held down or wiped out during early periods of infection, will bring us closer to ending HIV/AIDS,” says Robert Reinhard, CanCURE Community Liaison. “By filling an important gap in knowledge, this new study will advance research for an HIV cure.”

About the study
The research project was funded by the Canadian Institutes of Health Research (CIHR), the Canadian HIV Cure Enterprise (CanCURE) through a partnership between CIHR, the Canadian Foundation for AIDS Research (CANFAR) and the International AIDS Society (IAS), as well as by a pilot project from the FRQS AIDS and Infectious Disease Network. The study’s authors also include ?douard C?t? and Johanne Mercier from the IRCM, as well as Nick Aschman and Winfried Weissenhorn from the Universit? Grenoble Alpes in France. For more information on the study, please refer to the article published online by PLoS Pathogens

Findings from this study presented by Dr. Cohen on July 21 at the Vancouver Convention Centre as part of the 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention.

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Other Gene Tests for Cancer

Other than the BRCA1 and BRCA2 gene mutation test for breast and ovarian cancer, there are other gene-related tests available for cancer.

As an example, one such test that is available is for Lynch syndrome, a hereditary condition which comes with a family history of colon cancer and other types of cancer at a younger age. Those with the syndrome have a higher risk of colorectal and uterine (womb) cancers.

Like BRCA screening, the genetic screening test for Lynch is expensive and is recommended only for high-risk individuals with a strong family history of such cancers.

Trying to find the Lynch syndrome in the general population would be rather costly and not necessarily helpful, said Dr Lim Sheow Lei, a senior consultant at the department of gynaecological oncology at KK Women’s and Children’s Hospital.

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The field of cancer genetics is a rapidly evolving area.?? But things are changing quickly.? As genomic technology advances, the cost of sequencing the human genome is plunging, said Dr Lim. Just two weeks ago, a US company announced it was offering a much cheaper and easier way for women to get tested for the BRCA1 and BRCA2 genetic mutations.

Color Genomics* has begun selling a test (USD $249) that it said could accurately analyze a saliva sample for the mutations, as well as check for 17 other genetic variants that have been associated with a somewhat increased risk for cancer of the breast or ovaries.

Cancer can sometimes appear to “run in families” even if it is not caused by an inherited mutation.? Acquired mutations are the most common cause of cancer. These mutations occur from genes damaged during a person’s life. Smoking, viruses, and aging can damage genes and cause these mutations.

One such cancer caused by an acquired mutation is cervical cancFREE MS Art - Cancer Biology Ribboner, which stem from the human papilloma virus (HPV). Last year, the US Food and Drug Administration approved the HPV DNA test, manufactured by Roche, as a first-line primary screening test in women 25 and older. The geno-typing test detects DNA from 14 high-risk HPV types and specifically identifies HPV 16 and HPV 18, which carry the highest risk of cervical cancer. It can be used to help a healthcare professional assess the need for the woman to undergo additional diagnostic testing for cervical cancer. The test can also provide information about the patient’s risk for developing cervical cancer in the future.

Women who test positive for HPV 16 or HPV 18 should have a colposcopy, an examination using a device that illuminates and magnifies the cervix so a doctor can directly observe the cervical cells. Those who test positive for one or more of the 12 other high-risk HPV types should have a PAP smear to determine the need for a colposcopy. In a United States study of more than 47,000 women that compared HPV DNA tests with PAP smear tests, up to one in three women with cervical cancer had a normal PAP smear result.

Scientists and researchers are uncovering more genetic markers for other cancers.? The challenge is to know what to do with these pieces of information, how to interpret the multitude of newly uncovered mutations, work out the associated cancer risks and to manage the risks, said Dr Lim.

(Reprinted with license and permission from The Straits Times by Ng Wan Ching)
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*Information and link for Color Genomics does not constitute our endorsement of or any liability associated with the product, company or service.? Please consult a physician in case you believe you or someone you know may have cancer.

Halozyme: Update Following Type B FDA Meeting

Recent FDA meeting allows for potential marketing application based on progression free survival in pivotal Phase 3 pancreatic cancer study

Halozyme Therapeutics, Inc.,a biotechnology company developing novel oncology and drug-delivery therapies, today announced it plans to proceed with a Phase 3 clinical study (Study 301) of its investigational new drug PEGPH20 in patients with metastatic pancreatic cancer, using a design allowing for potential marketing application based on either progression free survival (PFS) or overall survival. The use of PFS as the basis for marketing approval will be subject to the overall benefit and risk associated with PEGPH20 combined with nab-paclitaxel (ABRAXANE ?) and gemcitabine therapy, including the:

  • Magnitude of the PFS treatment effect observed;
  • Toxicity profile;?and
  • Interim overall survival data.

The study will enroll patients whose tumors accumulate high levels of?hyaluronan?(HA)?? a?sugar?that?is sometimes more prevalent in the areas surrounding cancer cells. Halozyme recently discussed the study as part of a planned Type B meeting with the U.S. Food and Drug Administration (FDA).

bullseyeData discussed at the meeting focused on interim results from the company’s randomized Phase 2 study in pancreatic cancer, Study 202, which showed a doubling in median PFS in metastatic pancreatic cancer patients with high levels of HA who were treated with Halozyme’s investigational new drug PEGPH20 combined with nab-paclitaxel (ABRAXANE ?) and gemcitabine (9.2 months vs. 4.3 months in patients treated with nab-paclitaxel ABRAXANE ? and gemcitabine alone). The potential risk profile, including rate of thromboembolic events, was also discussed.? Additional?takeaways from the meeting include:

  • Halozyme?affirmed?plans?to enroll and evaluate high-HA patients using a companion diagnostic test; and
  • FDA provided feedback on the current?companion diagnostic approach and confirmed that an approved companion diagnostic strategy is required prior to Phase 3 study initiation.

“We are encouraged by the FDA’s feedback and their willingness to consider a novel primary endpoint such as PFS given the high unmet medical need in high-HA metastatic pancreatic cancer,” said Dr. Helen Torley, President and Chief Executive Officer. “We are committed to rapidly finalizing the Phase 3 protocol and developing the companion diagnostic regulatory filings required to initiate Study 301.” Based on this FDA feedback, the company is targeting the end of first quarter 2016 to initiate the Phase 3 study.

About Study 202 & PEGPH20microscope in laboratory
Study 202 (Halo 109-202) is a Phase 2 multi-center, randomized clinical trial evaluating investigational new drug PEGPH20 as a first-line therapy for treatment of patients with stage 4 metastatic pancreatic cancer. The primary outcome of the trial is to measure improvement in progression-free survival in patients receiving investigational new drug PEGPH20 in combination with gemcitabine and nab-paclitaxel compared to gemcitabine and nab-paclitaxel alone. A second primary endpoint will assess the thromboembolic event rate in the PEGPH20 treatment arm. Secondary endpoints also include objective response rate and overall survival. More information may be found at: http://oncologytrials.halozyme.com/pancreatic/.

PEGPH20 is an investigational PEGylated form of Halozyme’s proprietary recombinant human hyaluronidase under clinical development for the systemic treatment of tumors that accumulate hyaluronan. FDA granted orphan drug designation to PEGPH20 for treatment of pancreatic cancer and fast track for PEGPH20 in combination with gemcitabine and nab-paclitaxel for the treatment of metastatic pancreatic cancer. Additionally, the European Commission, acting on the recommendation from the Committee for Orphan Medicinal Products of the European Medicines Agency, designated investigational drug PEGPH20 an orphan medicinal product for the treatment of pancreatic cancer.

About Halozyme
Halozyme Therapeutics is a biotechnology company focused on developing and commercializing novel oncology therapies that target the tumor microenvironment. Halozyme’s lead proprietary program, investigational drug PEGPH20, applies a unique approach to targeting solid tumors, allowing increased access of co-administered cancer drug therapies to the tumor.? PEGPH20 is currently in development for metastatic pancreatic cancer and non-small cell lung cancer and has potential across additional cancers in combination with different types of cancer therapies. For more information, visit www.halozyme.com.

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FDA Approves Pulmozyme with eRapid Nebulizer

CF Patients See 2 – 3 Minute Treatment Times

The eRapid Nebulizer System (eRapid) from PARI has been approved as the first electronic nebulizer by the Food and Drug Administration to deliver Genentech’s Pulmozyme for cystic fibrosis treatment.? A huge improvement for cystic fibrosis patients, eRapid is able to reduce average treatment times with Pulmozyme from 6-8 minutes down to 2-3 minutes.? Both adult and pediatric patients showed a strong preference for eRapid over conventional nebulizers in a clinical study. FDA-Logo

“We have been pleased with eRapid’s fast treatment times in the lab and are excited that patients now have access to a much faster Pulmozyme therapy.? As the first electronic nebulizer to deliver Pulmozyme, eRapid is a true breakthrough for cystic fibrosis patients who take the therapy daily, often for years,”?said Lisa Cambridge, director of Medical Science and Pharmaceutical Alliances at PARI Respiratory Equipment, Inc.

“PARI was motivated to introduce eRapid to the US market based on encouragement from the Cystic Fibrosis Foundation and their input to have a general-use, electronic nebulizer that could improve therapy adherence. For many years, eRapid has been successfully distributed in Europe (as eFlow Rapid) with favorable feedback from patients with CF. In the Pulmozyme clinical trial, there was a 10:1 preference for eRapid in the pediatric group and a 20:1 preference in the adult group.? That confirmed our decision to bring eRapid to the US,” added Geoff A. Hunziker, president of PARI USA.

“After the successful results of a Phase IV study, we are confident that physicians will see that both pediatric and adult patients favor eRapid based on reduced treatment times, quiet operation, and its small, portable size.? We were also happy to see that patients were more satisfied with treatment and eRapid had a positive influence on adherence ? good for their overall cystic fibrosis management,” added Lisa Cambridge.? eRapid is available today by prescription through a select group of specialty pharmacies.? Visit www.pari.com or call 1-800-FAST-NEB to learn more.

Pulmozyme is indicated for daily administration along with standard therapies for the management of cystic fibrosis to improve pulmonary function.? For more information, visit http://www.pulmozyme.com/.

About eRapid Nebulizer System eRapid is an electronic nebulizer that enables quick and efficient inhalation that can greatly reduce a patient’s treatment burden. ?For more information on eRapid, please visit http://www.pari.com/.

About Cystic Fibrosis Cystic fibrosis, a life-threatening disease affecting 30,000 American patients, involves a genetic mutation that results in poorly hydrated, thickened mucus secretions in the lungs, as well as severely impaired mucociliary clearance.? Get more information about Cystic Fibrosis, visit http://www.cff.org

About PARI Respiratory Equipment, Inc. PARI is a leading, worldwide developer and manufacturer of fast and efficient aerosol delivery systems for patients with asthma, chronic lung disease, cystic fibrosis, RSV, VAP, and HAP.? PARI’s worldwide vision is to improve the lives of those affected by respiratory diseases and those who care for them.?PARI is considered the gold standard for aerosol delivery for nebulizer therapies.? Featured products include the PARI LC PLUS Reusable Nebulizer, Vortex Holding Chamber, and the drug-specific eFlow Technology platform.

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The Top 5 Recent Breakthroughs in Advanced Lung Cancer Treatment

Ross Camidge MD PHD ATOMICWe might need to look at our back catalogues for treatments we could retrospectively explore for effective predictive biomarkers with our more modern approaches. ?D. Ross Camidge, MD, PhD

A countdown of the top 5 breakthrough therapies in the treatment of advanced lung cancer was presented by D. Ross Camidge, MD, PhD, at the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology. Dr. Camidge is Director, Thoracic Oncology Clinical and Clinical Research Programs, and Associate Director for Clinical Research, University of Colorado Comprehensive Cancer Center, Aurora. He is also the Director for the newly minted ATOMIC Lung Cancer Consortium. He chose the following molecular therapies as his top choices for illustrating what the future of Lung cancer treatment will involve:

#5. Crizotinib

Dr. Camidge chose crizotinib(Xalkori) as a breakthrough therapy ?because of how it has exemplified the philosophy of one size does not fit all,? he said.

#4. Second-Generation ALK Inhibitors

The second-generation ALK inhibitors werechosen ?not because of their impressive activity post-crizotinib, but because of their progress in accurately defining how we capture data on benefit in central nervous system (CNS) disease,? Dr. Camidge explained.

#3. Third-Generation EGFR Inhibitors

Dr. Camidge identified the third-generation EGFR inhibitors ?because of what they are teaching us about understanding acquired resistance in order to effectively treat it,? he said.

#2. PD-1/PD-L1 Antagonists

Dr. Camidge singled out the inhibitors of programmed death receptor 1 (PD-1) and its ligand (PD-L1) as opening the door to immunotherapy but with the open question of whether they will really be a panacea or whether they have the potential to become a truly personalized medicine.

#1. Three Possible Future Breakthroughs

The?number 1 spot was shared by three ?mini-fantasies? about what future breakthroughs might be, based on the concepts of mining the past, intraoncogene heterogeneity, and affordable incremental benefit.

Explaining his interest in mining the past, Dr. Camidge said, ?We have walked away from a large number of targeted agents because they didn?t work when given to otherwise unselected lung cancer populations. However, in almost all of these cases, no attempt at robustly exploring predictive biomarkers was conducted,? he noted.

?Consequently, the classes of drugs may not truly be ineffective, and there may have been evidence of hypersensitive subpopulations ripe for re-exploration,? he continued. ?We might need to look at our back catalogues for treatments we could retrospectively explore for effective predictive biomarkers with our more modern approaches.?

As an example, he cited the class of drugs known as death receptor agonists. These drugs ?which directly stimulate apoptosis and worked exceptionally well in various preclinical models, were all dropped when a series of randomized phase II studies adding these agents to first-line chemotherapy failed to show an advantage.? But the nonprogressors in the experimental arms approached 15% of the population in several of the studies, he said. ?Unfortunately little or no tissue was collected in these studies so no predictive biomarkers could really be explored at the time.?

Dr. Camidge used KRAS as an example of intraoncogene heterogeneity. The most common mutation among adenocarcinomas of the lung, KRAS has been shown in preclinical and clinical studies to have tremendous heterogeneity. The trial design for the FAK inhibitor VS-6063 in KRAS-mutant lung cancer is ?at least starting to address this heterogeneity by exploring its benefit in four KRAS-mutant cohorts that have also been characterized with regard to their INK4a and p53 status to see if these contexts alter the response to the drug, based on relevant preclinical data,? Dr. Camidge said.

To explain affordable incremental benefit, he cited the REVEL study, which looked at the addition of ramucirumab (Cyramza), an antibody against VEGFR2, to standard second-line docetaxel. ?The addition of ramucirumab increased the response rate from 14% to 30% and the disease control rate from 53% to 64%, increased the progression free survival from 3.0 to 4.5 months, and increased the overall survival from 9.1 to 10.5 months,? Dr. Camidge reported.

?So with an unequivocally positive phase III study, adding a little to all major endpoints, we might want to be using this drug. But only if it, and drugs like it, are affordable, as one recurring problem has been in pricing a breakthrough as if it?s a game-changer and not just a way of offering a little incremental benefit to everyone.? If not affordable, ?these minor breakthroughs will never be practical to use in the real world,? he said.

Disclosures: Dr. Camidge has received honoraria from Pfizer, Genentech/Roche, Clovis, Aria, and Eli Lilly.

Reference
Camidge DR: The top five most promising molecular therapies on the horizon. Chicago Multidisciplinary Symposium in Thoracic Oncology. Presented October 31, 2014.

Source/Complete article by Charlotte Bath (The ASCO Post) is available at: http://www.ascopost.com/issues/december-1,-2014/top-5-breakthroughs-in-the-treatment-of-advanced-lung-cancer.aspx

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There May Soon Be A Vaccine For Breast Cancer

A study?on a new breast cancer vaccine developed at Washington University School of Medicine in St. Louis has found the treatment to be safe in patients with metastatic breast cancer. According to the press release,?the vaccine helped patients? immune systems attack breast tumor cells and also slowed the cancer?s progression.

By Dana Dovey? Release date: December 1, 2014

Breast cancer is the second most common cancer among American women, surpassed by only skin cancer. It?s estimated that around one in eight American women will develop some form of breast cancer during their lifetime, and sadly, the American Cancer Society estimates that around 40,000 women will succumb to the disease every year. Breast cancer detection and treatment is constantly improving, but with the possibility of a new vaccine, the day we beat breast cancer may be sooner than imagined.

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The vaccine works by helping a patient?s own body fight off breast cancer cells by pushing the immune system to target proteins called mammaglobin-A. These proteins are only found in breast tissue, and express themselves at abnormally high levels when there’s a tumor.? The vaccine prompts the immune system to target and destroy these proteins, which significantly slows breast cancer?s progression.

?Most physician scientists believe that breast cancer vaccines will be most successful for the treatment of patients with early-stage breast cancer, or for prevention of breast cancer in patients who are at high risk for developing breast cancer,? breast cancer surgeon and senior author of the study Dr. William E. Gillanders told?Medical Daily in an email. Mammaglobin-A is found in as many as 80 percent of breast cancer cases, he said. “In theory, this means we could treat a large number of breast cancer patients with potentially fewer side effects.?

The phase 1 trial was conducted to test the vaccine?s safety, and researchers were pleased to find that it passed with flying colors. Rash, tenderness at the vaccination site, and mild-flu like symptoms were the worst reactions recorded. “Despite the weakened immune systems in these patients, we did observe a biologic response to the vaccine while analyzing immune cells in their blood samples,” said Gillanders.

It?s important to note that this vaccine did not ?cure? the patient?s cancer or cause them to go into remission. ?Cancer vaccines are not currently used as a substitute for other therapies ? they are typically given in addition to other effective treatments,? Gillanders told Medical Daily.

Now that the vaccine has been shown to be safe for human use, the team will move on to a larger clinical trial. This time, they will use volunteers who were only recently diagnosed with breast cancer, and therefore would have much stronger immune systems. It?s believed that the stronger immune systems may provide even more impressive results.

?If we give the vaccine to patients at the beginning of treatment, the immune systems should not be compromised like in patients with metastatic disease,” Gillanders said. “We also will be able to do more informative immune monitoring than we did in this preliminary trial.?

Still, of the 14 volunteers in this most recent trial, about half showed no cancer progression one year after receiving the vaccine, which Gillanders says suggests ?that the cancer growth was slowed ? i.e. the progression-free survival was prolonged.?

The team now has the funding needed for the second phase of their study and will soon begin their new trial.

For more?information on translational research in breast cancer please visit the ABRCC website.
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OncoTherapy Network Highlights National Breast Cancer Awareness Month

Breast Cancer RibbonEvery October, National Breast Cancer Awareness Month [3] is observed to help spread the word about early detection. While screening is an integral part of breast cancer prevention, treatment options for thousands of patients diagnosed each year with breast cancer continues to be a focal point in oncology.

UBM Medica US announced that OncoTherapyNetwork [1], a leading online community to help oncologists and other clinicians gain a better understanding of the newest information available regarding the use of targeted therapies and immunotherapies, discusses some of the latest research on breast cancer treatment [2].

The featured articles below discuss some of the most recent research findings, including potential treatment options for both HER2-positive and triple-negative breast cancers:

? Neoadjuvant Carboplatin Boosts Targeted Therapy Responses in Triple-Negative Breast Cancer
The addition of neoadjuvant carboplatin to a regimen of taxane-anthracycline chemotherapy and targeted therapy substantially increased pathological complete responses in patients with stage II/III triple-negative breast cancer [4] (but not in patients with HER2-positive disease).

? Breast Cancer Vaccine Showing Promise in Women With HER2 Overexpression
Recent findings from a phase II randomized clinical trial demonstrates that a breast cancer vaccine known as GP2, may help at preventing disease recurrence in women with HER2 protein overexpression [5].

? Knockdown of CD24 May Enhance Efficacy of Targeted Agents in HER2-Positive Breast Cancer
Therapeutic targeting of CD24 may enhance the efficacy of targeted agents, such as trastuzumab and lapatinib, in treatment of human epidermal growth factor receptor 2 (HER2)-positive breast Cancer [6].

References:
1. www.oncotherapynetwork.com/?cid=pr10152014
2. www.oncotherapynetwork.com/breast-cancer-targets?cid=pr10152014
3. healthfinder.gov/nho/octobertoolkit.aspx
4. www.oncotherapynetwork.com/breast-cancer-targets/neoadjuvant-carboplatin-booststargeted-
therapy-responses-triple-negative-breast-cancer?cid=pr10152014
5. www.oncotherapynetwork.com/breast-cancer-targets/breast-cancer-vaccine-showingpromise-
women-her2-overexpression?cid=pr10152014
6. www.oncotherapynetwork.com/breast-cancer-targets/knockdown-cd24-may-enhanceefficacy-
targeted-agents-her2-positive-breast-cancer?cid=pr10152014
About UBM Medica US
Addressing today’s healthcare information needs, UBM Medica US, delivers strategic, integrated communications solutions and comprehensive reach — online, in print, via custom programs and live events. Improving the effectiveness of healthcare through information and education, UBM Medica US provides unbiased clinical, practical, and business information for physicians, providers and payers resulting in improved quality of care for patients around the world. Through journals, magazines, online communities, live and digital events, and other valuable resources, UBM Medica US also delivers comprehensive communication solutions for the pharmaceutical and related industries. Online communities include CancerNetwork.com, ConsultantLive.com, DiagnosticImaging.com, RheumatologyNetwork.com, OBGYN.net, PhysiciansPractice.com, PsychiatricTimes.com and SearchMedica.com. UBM Medica US is part of UBM Americas which, through a range of aligned interactive environments, both physical and digital ? increases business effectiveness for both customers and audiences through meaningful experiences, knowledge and connections.?For more information, visit www.UBMMedicaUS.com.

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Cancer Leaves a Common Fingerprint on DNA

Chemical alterations to genes appear key to tumor development
by Shawna Williams, Johns Hopkins Medicine – Release Date: August 26, 2014
(Displayed with permission from redOrbit.com – 2014 redOrbit)

Fast Facts:

  • Alterations to chemicals attached to DNA, known as epigenetic changes, affect how genes do their work and have been linked to colon cancer.
  • A new study of six different cancer types found distinctive epigenetic changes in all of them.
  • Conclusion: Epigenetic changes are key to cancer development.
DNA Image Courtesy of Thinkstock via RePubHub
DNA Image Courtesy of Thinkstock via RePubHub

Regardless of their stage or type, cancers appear to share a telltale signature of widespread changes to the so-called epigenome, according to a team of researchers. In a study of a broad variety of cancers, published online in Genome Medicine on Aug. 26, the investigators say they have found widespread and distinctive changes to chemical marks known as methyl groups attached to DNA. Those marks help govern whether genes are turned “on” or “off”, and ultimately how the cell behaves. Such reversible chemical marks on DNA are known as epigenetic, and together they make up the epigenome.

“Regardless of the type of solid tumor, the pattern of methylation is much different on the genomes of cancerous cells than in healthy cells,” says Andrew Feinberg, M.D., M.P.H., a professor of medicine, molecular biology and genetics, oncology, and biostatistics at the Johns Hopkins University School of Medicine. Feinberg led the new study along with Rafael Irizarry, Ph.D., a professor of biostatics at Harvard University and the Dana-Farber Cancer Institute. “These changes happen very early in tumor formation, and we think they enable tumor cells to adapt to changes in their environment and thrive by quickly turning their genes on or off,” Feinberg says.

Feinberg, along with Johns Hopkins University School of Medicine oncology professor Bert Vogelstein, M.D., first identified abnormal methylation in some cancers in 1983. Since then, Feinberg?s and other research groups have found other cancer-associated changes in epigenetic marks. But only recently, says Feinberg, did researchers gain the tools needed to find out just how widespread these changes are.

For their study, the research team took DNA samples from breast, colon, lung, thyroid and pancreas tumors, and from healthy tissue, and analyzed methylation patterns on the DNA. “All of the tumors had big blocks of DNA where the methylation was randomized in cancer, leading to loss of methylation over big chunks and gain of methylation in smaller regions,” says Winston Timp, Ph.D., an assistant professor of biomedical engineering at Johns Hopkins. “The changes arise early in cancer development, suggesting that they could conspire with genetic mutations to aid cancer development,” he says.

The overall effect, Feinberg says, appears to be that cancers can easily turn genes “on” or “off” as needed. For example, they often switch off genes that cause dangerous cells to self-destruct while switching on genes that are normally only used very early in development and that enable cancers to spread and invade healthy tissue. “They have a toolbox that their healthy neighbors lack, and that gives them a competitive advantage,” Feinberg says.

“These insights into the cancer epigenome could provide a foundation for development of early screening or preventive treatment for cancer,” Timp says, suggesting that the distinctive methylation “fingerprint” could potentially be used to tell early-stage cancers apart from other, harmless growths. Even better, he says, would be to find a way to prevent the transition to a cancerous fingerprint from happening at all.

Other authors on the paper are Hector Corrada Bravo of the University of Maryland, College Park, and Oliver G. McDonald, Michael Goggins, Chris Umbricht and Martha Zeiger, all of The Johns Hopkins University.

The study was funded by the National Human Genome Research Institute (grant number HG003223), the National Cancer Institute (grant number CA054358), the National Institute of General Medical Sciences (grant numbers GM083084 and GM103552) and the National Center for Research Resources (grant number RR021967).

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Advantages and Challenges of Conducting Clinical Research in South Africa

Get To Know The South African Healthcare System

The South African healthcare system consists of public healthcare, which is financed and managed by the South African government, and private healthcare, which is primarily funded by health insurance and private direct fee for service payments. Private healthcare consumes more than 50% of total healthcare spending in South Africa, but only services about 20% of the population able to afford health insurance or direct funding of their healthcare needs.

South Africa Flag RoundThe Attraction of South Africa as Clinical Research Destination

South Africa is classified internationally as a developing country and is often viewed by the less-informed as a poorly developed African country. This is far from the truth.? South Africa has a long history of conducting clinical research; this translates to interest of the medical profession in furthering their knowledge and remaining at the cutting edge of medical development. This is a good indication of the pool of experienced clinical research staff available for research, which is growing and developing as the research environment changes over the years. Clinical research experience is of paramount importance in the South African research environment: it is a regulatory requirement that investigators may only participate as principal investigator after having participated in at least two different clinical trials as a sub-investigator.

A Sophisticated Infrastructure and Clinical Trial Support System

South Africa has a sophisticated infrastructure and clinical trial support system available. Laboratory support to process and analyze blood and tissue samples is readily available in all the large metropolitan cities in South Africa. Most, if not all, of the major laboratories have a clinical trial division that specifically caters for the clinical trial environment, and usually have some partnership/working relationship with the large multinational analytical laboratories. All FREEPIK Medical Imagesthe clinical laboratories are audited and accredited by SANAS. These facilities meet all of the international standard requirements.

Product Depots with Strict Control Mechanisms in Place

As South Africa is located quite a distance from the major manufacturing facilities in the USA, Europe and Asia, investigational product depots are often used to import and distribute clinical trial products to site. These facilities adhere to all international packaging and manufacturing (GMP) and clinical trial requirements (GCP). As they generally receive, store, and distribute clinical trial investigational product for a number of different studies and companies, they have very strict control mechanisms in place to ensure confidentiality and safety of clinical trial product. They are able to manage all types of investigational product at all temperature ranges.

Interested in more in-depth information on this topic? Download our complete article from the May 2014 Journal for Clinical Studies:

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The New Treatment Paradigm in Cancer Research

Dr J S Macdonald MDDr. John S. Macdonald
Senior Consultant for The Oncology Consortia of CRITERIUM, INC.

In the past, typical anti-cancer systemic therapies that worked, albeit poorly, did so by killing cancer cells only slightly better than they killed normal cells. There were relatively few of these drugs and they were given to patients with all kinds of cancers. This toxic therapy could be depended upon to make patients sick all the time while rarely making cancers significantly improve.? To effectively develop these new treatments, clinical investigators must not only be excellent physicians but also be first rate molecular and cellular biologists.

CHEMOTHERAPEUTIC AGENTS KILL MORE CELLS THAN THEY SHOULD
The classic chemotherapeutic agents are relatively non specific toxins that function by killing or at least seriously injuring cells. These agents cause significant toxicity to patients because all or most of the cells in the body are injured by these drugs. A successful chemotherapeutic agent kills cancer cells a little better than it kills normal cells.

CHEMOTHERAPY MAKING A CANCER COMPLETELY DISAPPEAR IS RARE
One of the real negative aspects of chemotherapy is that all patients receiving a drug experience toxicity which may be life threatening, but only a minority of patients with cancer will actually have treatment make the tumor regress. Having chemotherapy make a cancer completely disappear with treatment with the therapy producing a CR or complete response, is rare. The final phase III trials required to show that a new treatment is equal to or superior to a standard therapy, require hundreds of patients most of whom will be made sick by the therapy but not get any anti-tumor benefit.

CLASSIC CHEMOTHERAPY PRODUCES UNWANTED ADDITIONAL EFFECTS
Finally since classic chemotherapy agents are toxins they may produce late effects such as second cancers and major organ (bone marrow, kidney, liver, lung, etc.) damage in patients who receive treatment and or cured of their original cancers. So the bottom line with classic chemo is that these are agents that are always toxic, rarely curative, require hundreds of patients on clinical trials to demonstrate efficacy and may result in serious late effects.

Recently this paradigm of toxic relatively ineffective cancer therapies is changing. Because of increased knowledge of molecular biology and molecular genetics, more specific targeted therapies that are less toxic to normal cells are being developed. Some dramatic improvements in survival have been reported with such treatments.

IN TARGETED THERAPIES, ONLY CANCER CELLS ARE DAMAGED
AND NORMAL CELLS ARE SPARED
The key factors that make targeted cancer therapies and immunotherapy different from and in theory superior to chemotherapy are that these treatments dependent upon specific anti-tumor effects. In other words in the ideal situation only? the cancer cells are injured or killed with a targeted approach or an immunotherapy approach. Thus if a target exists only in tumor cells or is over expressed in tumor cells, then a targeted therapy only affects the cancer cell and does minimal if any damage to normal cells. Ideally the result is tumor death and no normal cell toxicity. Likewise with immunotherapy, the only cells damaged would be the cells (tumor cells) carrying the antigen or marker that the immune system recognizes. Again the result is that cancer cells are damaged and normal cells are spared.

TARGETED THERAPIES ARE MORE EFFICIENT AND LESS TOXIC
The factor to keep in mind is that the clinical development of more targeted therapies should clearly be much more efficient than development of chemotherapy. Only patients with the specific target are entered in clinical trials so the likelihood of benefit is increased. Targeted or immunotherapeutic treatments may be active against the tumor at dose levels that are minimally toxic. Thus small targeted relatively non toxic trials may be used in development of newer approaches to cancer treatment.

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