For cancer patients with HIV, immunotherapy appears safe

A new category of immunotherapies called checkpoint inhibitors that has been highly effective against many different cancers appears safe to use in patients with both advanced malignancies and HIV, a population excluded from earlier trials of such therapies, according to an early-phase trial.

Study Principal Investigator, Dr. Thomas Uldrick of the HIV & AIDS Malignancy Branch at the National Cancer Institute, will present late breaking results from the first 17 patients on a phase I study of pembrolizumab in patients with HIV and advanced cancers Friday at the Society for Immunotherapy of Cancer’s annual meeting in National Harbor, Maryland. The ongoing, multi-site study is being conducted by the NCI-funded Cancer Immunotherapy Trials Network, which is headquartered at Fred Hutchinson Cancer Research Center.

Cancer has become the leading cause of death for people with HIV. But until now, they and their physicians have had little data to guide them on whether they can safely use powerful new anti-cancer drugs called immune checkpoint inhibitors.

“During the development of these drugs, people with HIV were routinely excluded from studies due to concerns that they would not tolerate these medications or perhaps not benefit from them because of their underlying HIV and associated immune dysfunction,” Uldrick said. “The most important first step was to show that this class of drug would be safe in cancer patients with HIV.”

Study participants — who were on standard antiretroviral therapy to control their HIV infections and had various cancers that had failed to respond to standard therapies — received pembrolizumab (Keytruda), known since 2015 as “the Jimmy Carter drug” after it swiftly beat back melanoma that had spread to the former president’s brain and liver.

Pembrolizumab belongs to a type of immunotherapy that blocks a braking system cancers use to tamp down the immune response. Checkpoint inhibitors have been extremely effective in some patients with advanced cancers otherwise thought untreatable. The treatments have received U.S. Food and Drug Administration approval for melanoma, lung cancer, head and neck cancer, Hodgkin’s lymphoma, and kidney and bladder cancers.

“These drugs are the backbone of cancer immunotherapy at present and have been shown to be effective in subsets of virtually every different kind of cancer,” said Fred Hutch immunotherapy researcher Dr. Martin “Mac” Cheever, who leads the Cancer Immunotherapy Trials Network and is senior author of the new study. “For patients with HIV who are using effective antiretroviral therapy and have cancers for which these drugs are approved, there’s no reason not to consider these drugs as standard therapy.”

HIV and cancer

From the earliest days of the AIDS pandemic, Kaposi sarcoma — a rarely seen cancer until then — was one of a trio of cancers known as AIDS-defining malignancies. It, non-Hodgkin lymphoma and, in women, cervical cancer, often signaled that a person’s HIV infection had progressed to full-blown AIDS. People did not die of AIDS, per se. They died of one of these cancers or of infections like pneumocystis pneumonia and toxoplasmosis that took advantage of a weakened immune system.

Since the advent of antiretroviral therapy for HIV in 1996, full-blown AIDS and AIDS deaths have dropped dramatically. But the association between HIV and cancer remains, and not just with the traditional AIDS-defining malignancies. A large study published in the journal Annals of Internal Medicine in 2015 found higher cancer incidence across the board in HIV patients, including lung cancer and Hodgkin lymphoma.

“Globally, more than 35 million people are infected with HIV, and cancer is the number one reason they are dying,” Uldrick said. “Establishing proven effective regimens to manage cancer in people with HIV is critically important.”

The ongoing study will enroll up to 36 patients, and there are plans to include more patients with Kaposi sarcoma, a cancer for which checkpoint inhibitors have not been studied. It is one of the leading causes of cancer deaths in sub-Saharan Africa — where HIV rates are high — and new treatments are sorely needed.

Further study in Kaposi sarcoma

Kaposi sarcoma is caused by the Kaposi sarcoma herpes virus (also known as human herpesvirus 8, or HHV-8) and most commonly appears as lesions on the skin. KSHV can also cause two other B-cell tumors, primary effusion lymphoma and a form of multicentric Castleman disease. Additionally, it can infect blood cells and spread through the bloodstream to infect other cells in the body, Uldrick said.

Also to be presented Friday is the death of one patient later in the study who had Kaposi sarcoma. The death is still being evaluated but was likely due to dissemination of KSHV. Uldrick and Cheever said review of the case suggests the patient had a history of symptomatic KSHV viremia, and the study has been changed to exclude such patients in the future and provide specific guidelines for management should new symptomatic KSHV viremia be observed.

Six other study participants with Kaposi sarcoma or primary effusion lymphoma have been treated on this study. None has experienced similar problems, and some have benefitted from therapy, Uldrick said.

“We do not believe that this takes away from the safety message in patients with HIV and other, better studied cancers,” Uldrick said. “However, more experience is clearly needed in treating KSHV-associated diseases with checkpoint inhibitors.”

A passion to ‘change the culture’

Although the NCI has recommended including people with HIV in immunotherapy clinical trials for a decade, virtually every industry-sponsored study over the last five years excluded them, according to a review by Uldrick and others published in the Journal of Clinical Oncology. Uldrick believes that reluctance to include people with HIV in cancer immunotherapy studies dates back to a time when patients were still dying of opportunistic infections and antiretroviral therapies were more toxic than they are today.

As a physician-scientist who focuses on immunology, virology and cancer, Uldrick became frustrated with the lack of data.

“The culture was slow to change,” he said. “It was preventing the advance of appropriate clinical therapies.”

Dr. Holbrook Kohrt, a Stanford oncologist and researcher, shared that frustration. Kohrt instigated the current clinical trial, according to Cheever, driven by his boyhood experience being one of only two hemophiliacs in a special summer camp who did not die of AIDS. (The genetic disorder impairs the blood’s clotting ability and requires infusions of lifesaving clotting factor, which at that time was made from the pooled blood of tens of thousands of donors. Before a test was developed to detect HIV in blood, about half the hemophiliacs in the United States died of AIDS from infected clotting factor.)

“Holbrook had three patients early on with malignancies that he thought would benefit from [checkpoint inhibitors] and could not get access to the drug because they had HIV,” Cheever said. “He was passionate about this study because he was a passionate individual and physician. But he was also influenced by his experience as someone with hemophilia who lost so many peers to HIV.”

Kohrt died in 2016 from complications of hemophilia. He is named as an author of the study.

“He would have predicted these results,” Cheever said.

Getting out the message

The ongoing study is now being conducted at eight sites, each of which includes physician-researchers with expertise in both cancer and HIV. A majority of the early patients were enrolled on the trial through Uldrick’s group at the NCI Intramural Research Program in Bethesda, Maryland.

Uldrick will continue to lead the study after he leaves the NCI to become deputy head of Fred Hutch Global Oncology on Dec. 1.

He and Cheever are hoping that these early results lead to additional studies of checkpoint inhibitors in people with HIV and malignancies, especially those cancers that are more prevalent in people with HIV such as Kaposi sarcoma and cancers caused by another virus, human papillomavirus, such as cervical cancer.

In the meantime, the researchers intend to talk about their findings at multiple scientific communities so that people with HIV and their physicians become aware of the data.

“We’d recommend that patients with HIV and malignancy be considered for this therapy if it’s approved for their particular cancer,” Uldrick said.

Study Finds a New Way to Shut Down Cancer Cells’ Ability to Consume Glucose

Cancer cells consume exorbitant amounts of glucose, a key source of energy, and shutting down this glucose consumption has long been considered a logical therapeutic strategy. However, good pharmacological targets to stop cancers’ ability to uptake and metabolize glucose are missing. In a new study published in Cell Reports, a team of University of Colorado Cancer Center researchers, led by Matthew Galbraith, PhD, and Joaquin Espinosa, PhD, finally identifies a way to restrict the ability of cancer to use glucose for energy.

Over-expression of the gene CDK8 is linked to the development of many cancers including colorectal cancer, melanoma, and breast cancer, where it regulates pathways that drive the growth and survival of cancer cells. Although a number of drugs aimed at blocking CDK8 activity are currently being developed, it is not yet clear how effective they are at treating various cancers. Galbraith and Espinosa have been working to better understand the role of CDK8 in cancer biology in the hopes of aiding the introduction of CDK8-based therapies as cancer treatments.

Their most recent study, which was funded in part by the Cancer League of Colorado and the Mary Miller and Charlie Fonfara-Larose Leukemia in Down Syndrome Fund, demonstrates that CDK8 plays a critical role in allowing cancer cells to use glucose as an energy source.

The finding takes place against the backdrop of the tissue conditions in which tumors grow – as cancer cells rapidly multiply, their growth often outstrips their blood supply, leading to depletion of oxygen (i.e. hypoxia) and other nutrients such as glucose. In 2013, the group published a paper showing that CDK8 is important for activation of many genes switched on in hypoxic conditions. During adaptation to these conditions, cancer cells must alter their metabolism to consume more glucose through a process called glycolysis. In fact, many cancer cells have permanent increases in glycolysis, maintained even in conditions of plentiful oxygen, a phenomenon known as the Warburg effect, which was described as far back as 1924. Consequently, many cancers are heavily dependent on glucose metabolism for their growth and survival. This is true to the point that doctors use glucose isotopes and PET scans to pinpoint the exact location of a tumor and its metastases within the human body – where there are abnormally high levels of glucose being used, chances are there is a cancerous growth.

When Galbraith used a sophisticated chemical genetics approach to specifically switch off CDK8 activity in colorectal cancer cells, he saw that the cells failed to activate glycolysis genes and took up much less glucose. He confirmed this in experiments showing that blocking CDK8 activity leads to a lower rate of glucose use.

“Because of this role of CDK8 in glycolysis, I reasoned that the cells with impaired CDK8 activity should be more susceptible to drugs that block glycolysis,” Galbraith says. Sure enough, treating cancer cells with drugs that block both CDK8 and glycolysis slowed their growth more effectively than either approach alone.

“These are very exciting discoveries. The Warburg effect and consequent addiction to glucose is a hallmark of cancerous tissues, something that distinguishes cancer cells from most normal tissues. Therefore, combining drugs that block CDK8 activity with those that block glycolysis may enable specific targeting of cancer cells without harmful effects on normal cells,” says Espinosa, the paper’s senior author.

The team was recently awarded a grant from the Denver chapter of Golfers Against Cancer to advance their findings through pre-clinical research in mouse models, a necessary step to test the clinical value of this new strategy targeting CDK8 and glucose metabolism.

FDA Approves the Roll-Over Combination Study with Checkpoint Inhibitor Immunotherapies to Allow Continued Access to BriaVax™ in Patients with Advanced Breast Cancer

The FDA has approved the roll-over combination study of the investigational breast cancer vaccine, BriaVax™ with pembrolizumab {Keytruda; manufactured by Merck & Co., Inc. or ipilimumab {Yervoy; manufactured by Bristol-Myers Squibb Company for patients previously treated with BriaVax™ from the ongoing Phase I/IIa Clinical Trial in Advanced Breast Cancer.

BriaVax™ is a whole-cell breast cancer vaccine genetically engineered to release granulocyte-macrophage colony-stimulating factor (GM-CSF), a substance that activates the immune system by allowing the body to recognize and eliminate cancerous cells by inducing tumor-directed T cell and potentially antibody responses.

This roll-over combination study allows the patients who did not respond to BriaVax™ (monotherapy) treatment to be treated and continue to receive the potential clinical benefits of the vaccine in combination with either pembrolizumab or ipilimumab. This approach is based on the hypothesis that both pembrolizumab and ipilimumab may improve the anti-tumor activity of vaccine in patients with advanced breast cancer. Safety and efficacy data will be evaluated.

“We are very excited to evaluate the effects of BriaVax™ with other approved anti-tumor immunotherapeutic agents. We expect this study to extend and potentiate the clinical benefits of BriaVax™ in advanced breast cancer patients,” stated Dr. Williams, BriaCell’s President & CEO in a press release. “We look forward to expanding our clinical study and exploring potential immunotherapy partnerships with leading pharmaceutical companies in the future, and we are pleased with the FDA decision,” Dr. Williams added.

The clinical investigators will work closely with Cancer Insight, LLC, BriaCell’s contract research organization, to manage the clinical and regulatory aspects of the clinical trial for the roll-over combination study of BriaVax™ on behalf of BriaCell. More information on the roll-over combination study of BriaVax™ with either ipilimumab or pembrolizumab will be available on ClinicalTrials.gov (Study identifier: BRI-ROL-001).

Manufactured by Merck & Co., Inc., KEYTRUDA® (pembrolizumab) is a prescription medicine that may treat certain cancers by working with the immune system. It has been approved for the treatment of a number of cancer indications excluding breast cancer.

Manufactured by Bristol-Myers Squibb Company, YERVOY® (ipilimumab) is a prescription medicine used in adults and children 12 years and older to treat melanoma (a kind of skin cancer) that has spread (metastatic) or cannot be removed by surgery (unresectable). It is a monoclonal antibody that works to activate the immune system and enabling them to recognize and destroy cancer cells.

BriaVax™ is a whole-cell breast cancer vaccine genetically engineered to release granulocyte-macrophage colony-stimulating factor (GM-CSF), a substance that activates the immune system. Previously, a small Phase I study documented very prompt and near complete regression of metastatic breast cancer deposits in the breast, lung, soft tissue, and even the brain.

The ongoing open-label Phase I/IIa study will evaluate BriaVax™ in up to 40 advanced breast cancer patients. This trial is listed in ClinicalTrials.gov as NCT03066947. The trial is being conducted along with the co-development of BriaDx™, our companion diagnostic test. The interim data for the first 10 patients is expected by the first quarter of 2018.

BriaCell is an immuno-oncology focused biotechnology company developing a targeted and safe approach to the management of cancer. BriaCell’s mission is to serve late-stage cancer patients with no available treatment options.

Immunotherapy has come to the forefront of the fight against cancer, harnessing the body’s own immune system in recognizing and selectively destroying the cancer cells while sparing normal ones. Immunotherapy, in addition to generally being more targeted and less toxic than commonly used types of chemotherapy, is also thought to be a strong type of approach aimed at preventing cancer recurrence.

The results of two previous Phase I clinical trials (one with the precursor cell line not genetically engineered to produce GM-CSF and one with BriaVax™) have been encouraging in patients with advanced breast cancer. Most notably, one patient with metastatic breast cancer responded to BriaVax™ with substantial reduction in tumor burden including lung and brain metastases. The company is currently conducting a Phase I/IIa clinical trial for BriaVax™ in patients with advanced breast cancer whose disease has progressed following at least one prior treatment course.

This trial is listed in ClinicalTrials.gov as NCT03066947.  The trial is being conducted along with the co-development of BriaDx™, our companion diagnostic test. The interim data for the first 10 patients is expected by the first quarter of 2018.

In a previous Phase I setting, a patient with metastatic breast cancer responded to BriaVax™ with objective reduction in tumor burden. To expand on this finding, after updating the clinical protocol of the original investigational new drug (IND) application, an open-label Phase I/IIa clinical trial enrolling up to 40 late stage breast cancer patients with recurrent and/or metastatic disease has been launched. Patients will be administered BriaVax™ every two weeks for the first month of treatment, then monthly up to one year.

The primary objective of the Phase I/IIa clinical trial is to evaluate the safety of BriaVax™ in study subjects, and the principal secondary objective is an evaluation of the tumor size reduction. Tumor response will be monitored every three months during the study. The trial will also evaluate progression-free survival (PFS) and overall survival (OS).

For additional details regarding the clinical trial, please visit:
https://www.clinicaltrials.gov/ct2/show/NCT03066947

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.”

Cancer trial led by University of Minnesota Medical School’s Dr. Clark Chen shows promise

New data from a Phase I clinical trial led by Clark Chen, M.D., Ph.D., Lyle French Chair in Neurosurgery and Head of the University of Minnesota Medical School Department of Neurosurgery shows more than a quarter of patients with recurrent high-grade glioma, a form of brain cancer, were alive more than three years after treatment.

“Given the deadly nature of this disease, three-year survival is rarely reported in the recurrent setting. It is notable that the survival benefit was seen across a range of patients and not just limited to patients with specific genetic mutations,” said Chen. “This finding indicates that many patients could benefit from this treatment.”

As Chen explained at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics two steps were involved in the treatment of the 56 patients who participated in this clinical trial. First, patients were injected with Toca 511, which is a replicating virus that only infects actively dividing tumor cells. Once inside the cancer cell, the virus delivered a gene for an enzyme, cytosine deaminase (CD). As the virus began to replicate and spread to other cancer cells, it programmed them to make CD. Next, patients received a pill, Toca FC, which is an inert compound. Once inside the cancer cell, CD converted Toca FC into the anticancer drug 5-fluorouracil, which killed the cancer cell. In addition to destroying the cancer cells, 5-fluorouracil killed certain immune suppressive myeloid cells, thus boosting the patient’s immune system to recognize and attack the cancer cells.

“The treatment we tested in this trial delivers local chemotherapy specifically to the brain tumor. Toca 511 and Toca FC work together to turn the brain tumor into a factory that produces an anticancer drug while also activating the immune system through a combination of mechanisms, which together work to attack the cancer,” Chen said.

Dr. Chen also noted that five patients are experiencing a durable complete response with a median of at least 35.7 months. Within a subgroup of 23 patients, there were an additional five patients who achieved stable disease, bringing the number of patients who derived benefit from Toca 511 to 10 (or 43.4 percent of the patients who underwent Toca 511 therapy).

According to Chen, the median survival in this trial is nearly double that of historical data. In the subgroup, median survival was 14.4 months, compared to approximately eight months for historical controls.

“Brain cancer is one of the deadliest cancers, giving urgency to finding an effective treatment,” Chen said. “The 160,000 people diagnosed with high-grade gliomas worldwide each year–and high-profile cases including U.S. Senator John McCain, Senator Edward Kennedy, and Beau Biden–demonstrate the high unmet need of this disease. The data generated in the Toca 511 research provides hope for patients with brain cancer and their families.”

This study was a single arm trial without a control group which acted as a limitation. “The ongoing randomized phase II/III trial will be important to confirm the promising safety and efficacy results reported in this Phase I study,” Chen noted.

Public-Private Consortium Aims to Cut Preclinical Cancer Drug Discovery from Six Years to Just One

Scientists from two U.S. national laboratories, industry and academia today launched an unprecedented effort to transform the way cancer drugs are discovered by creating an open and sharable platform that integrates high-performance computing, shared biological data from public and industry sources and emerging biotechnologies to dramatically accelerate the discovery of effective cancer therapies.

The goal of the consortium – Accelerating Therapeutics for Opportunities in Medicine (ATOM) – is to create a new paradigm of drug discovery that would reduce the time from an identified drug target to clinical candidate from the current approximately six years to just 12 months. ATOM aims to transform cancer drug discovery from a time-consuming, sequential and high-risk process into an approach that is rapid, integrated and with better patient outcomes — using supercomputers to pretest many molecules simultaneously for safety and efficacy.

The consortium comprises the Department of Energy’s Lawrence Livermore National Laboratory (LLNL), GSK, the National Cancer Institute’s Frederick National Laboratory for Cancer Research (FNLCR), and the University of California, San Francisco (UCSF). ATOM welcomes additional public and private partners who share the vision.

“The goals of ATOM are tightly aligned with those of the 21st Century Cures Act, which aims in part to enable a greater number of therapies to reach more patients more quickly,” said FNLCR Laboratory Director David Heimbrook. “Although initially focused on precision oncology – treatments targeted specifically to the characteristics of the individual patient’s cancer – the consortium’s discoveries could accelerate drug discovery against many diseases.”

ATOM will develop, test and validate a multidisciplinary approach to drug discovery in which modern science, technology and engineering, supercomputing simulations, data science and artificial intelligence are highly integrated into a single drug-discovery platform that can untimately be shared with the drug development community at large.

“As we have learned more about what modern supercomputers can do, we’ve gained confidence that this approach can make a big difference in creating medicines,” said John Baldoni, senior vice president, R&D at GSK. “We must do all that we can to reduce the time it takes to get medicines to patients. GSK is working to set a precedent with pharmaceutical companies by sharing data on failed compounds.”

GSK will initially contribute chemical and in vitro biological data for more than 2 million compounds from its historic and current screening collection, as well as preclinical and clinical information on 500 molecules that have failed in development but could help accelerate development of new compounds by providing knowledge about the underlying biology of candidate compounds and that of the human body. Combined with data on successful drugs, GSK’s offering represents a broad base of information for ATOM researchers. In addition, GSK will provide expertise in drug discovery and development, computational chemistry and biology.

The ATOM team will combine data provided by GSK with publicly available data, and that of future consortium members, to generate new dynamic models that can better predict how molecules will behave in the body compared to the current iterative and time-consuming practices. In this effort, LLNL will contribute its best-in-class supercomputers, including its next-generation system Sierra, as well as its expertise and innovative approaches to modeling and simulation, cognitive computing, machine learning and algorithm development. More broadly, by tackling the ambitious challenge of cancer therapies, ATOM will drive technologies vital to the core missions of the Department of Energy and National Nuclear Security Administration (NNSA).

“ATOM is a novel public-private partnership that draws on the lab’s unique capabilities to create a paradigm change in drug development,” said LLNL Director Bill Goldstein. “It will help to strengthen U.S. leadership in high-performance computing and, by speeding the discovery of therapeutics, contribute to biosecurity.”

For its part, FNLCR will contribute from its wealth of scientific expertise in precision oncology, computational chemistry and cancer biology, as well as support for open sharing of data sets and predictive modeling and simulation tools. UCSF will provide expertise from a long history of innovation in drug discovery and medicine to improve the lives of patients.

“We at UCSF are eager to lend our expertise to this effort,” said UCSF Chancellor Sam Hawgood, MBBS. “UCSF scientists and clinicians have long been leaders in drug discovery, therapeutics, and cancer biology with the UCSF Helen Diller Family Comprehensive Care Center among the top-ranked cancer institutes in the country. Our role with ATOM is therefore in lock step with UCSF’s mission of advancing health worldwide.”

ATOM welcomes additional public and private partners who share the vision of the consortium, which will have physical headquarters in the Mission Bay neighborhood of San Francisco, adjacent to UCSF’s newest campus.

Proton therapy for prostate cancer is advantageous to imrt according to new study

Proton therapy treatment for prostate cancer is associated with higher survival rates and decreased risk of complications compared to intensity-modulated radiation therapy (IMRT) according to a new study by researchers at the Northwestern Medicine Chicago Proton Center. The study is being presented at the 4th Annual Particle Therapy Co-Operative Group North-America (PTCOG-NA) Conference on October 25 in Chicago.

“This new evidence supports that proton therapy is at least as good as standard radiation therapy and may be significantly better in some areas, especially protecting normal tissue outside of the prostate,” said the study’s lead author William Hartsell, MD, medical director of the Northwestern Medicine Chicago Proton Center. “In addition, the evidence shows that proton therapy is advantageous for younger patients who we are most concerned about developing secondary cancers later in life.”

Proton therapy uses protons – heavy, positively charged atomic particles – instead of the standard X-rays used in conventional radiation therapy. Protons deposit much of their energy, or dose, directly in the tumor and then stop, whereas conventional radiation continues to deposit the dose beyond the tumor.

Dr. Hartsell and colleagues reviewed the records of over 28,000 IMRT patients and 851 proton patients who received treatment from 2006-2012, using the Medicare and SEER (Surveillance, Epidemiology and End-Results Reporting) national databases. The proton patients were matched to IMRT patients in a 1:5 matching process using several parameters, including comorbidity index, cancer stage, tumor grade, adjuvant chemo/hormone therapy, age, zip code and ethnicity.

Using the matched patient cohort, the 5-year overall survival rate for proton therapy was 93.25% compared to 88.43% for IMRT. For the matched group of intermediate risk patients, the gap was slightly greater with a 5-year overall survival for proton therapy patients of 93.65% compared to 88.27% for IMRT.

The study also reviewed the incidence of complications and found significantly more patients with bladder, endocrine or “other” complications with IMRT compared to protons. In addition, there were greater numbers of patients with secondary malignancies with IMRT. 10.5% for IMRT compared to 6.1% for proton therapy at 5 years.

“This study is a significant update on the efficacy of proton therapy for prostate cancer. Many insurance companies are relying on outdated and incorrect data to determine coverage,” said Dr. Hartsell.

Insights from a rare genetic disease may help treat multiple myeloma

A new class of drugs for blood cancers such as leukemia and multiple myeloma is showing promise. But it is hobbled by a problem that also plagues other cancer drugs: targeted cells can develop resistance. Now scientists, reporting in ACS Central Science, have found that insights into a rare genetic disease known as NGLY1 deficiency could help scientists understand how that resistance works — and potentially how drugs can outsmart it.

A class of compounds called proteasome inhibitors that include bortezomib and carfilzomib — both approved by the U.S. Food and Drug Administration — have been effective at treating certain types of blood cancers. The drugs work by jamming some of cancer cells’ machinery to induce cell death. But the drugs have been limited by cancer cells ability to development resistance, as well as the inhibitors inability to fight solid tumors effectively. Studies have suggested that resistance could be linked to a protein called Nrf1. When proteasome inhibitors go into action, Nrf1 is spurred into overdrive to restore the cells’ normal activities and keep them alive. If researchers could figure out how to block Nrf1, they might be able to address the resistance problem. Carolyn Bertozzi and colleagues, through studying NGLY1 deficiency, a seemingly unrelated condition, may have hit upon an approach to do this.

The researchers were investigating how lacking the enzyme NGLY1 causes a host of debilitating symptoms. They found that NGLY1 is responsible for activating Nrf1, the protein that is suspected of weakening proteasome inhibitors’ effectiveness against cancer. Further testing showed that dampening NGLY1 allowed a proteasome inhibitor to continue doing its work killing cancer cells without interference from Nrf1. This finding, the authors note, holds great promise for the development of combination therapeutics for blood cancers in the future.

Proton Therapy Lowers Treatment Side Effects in Pediatric Head and Neck Cancer Patients

Pediatric patients with head and neck cancer can be treated with proton beam therapy (PBT) instead of traditional photon radiation, and it will result in similar outcomes with less impact on quality of life. Researchers from the Perelman School of Medicine at the University of Pennsylvania as well as Children’s Hospital of Philadelphia analyzed cases of pediatric head and neck cancer treated with PBT between 2010 and 2016 and found similar rates of tumor control and lower rates of toxicity than what is historically expected from photon radiation. They published their findings today in the journal Pediatric Blood and Cancer.

Cancers of the head and neck account for about 12 percent of all pediatric cancers, and they are generally different tumor types than those that affect adults. For solid tumors like neuroblastoma, thyroid cancer, and soft tissue sarcomas, treatment usually involves a combination of therapies including chemotherapy, radiation, and surgery. Post-operative radiation can be critical, since surgeons may not be able to completely remove all cancer given the complexity of the head and neck region.

The area’s sensitivity also means the effects of treatment can lower patient quality of life due to symptoms including loss of appetite, difficulty swallowing, or mucositis – in which ulcers form in the digestive tract, usually in reaction to chemotherapy or radiation.

“These concerns are especially important to address in pediatric patients, since they’re still developing and may need to deal with any adverse effects for the rest of their lives. This study shows that protons may be an important tool in improving quality of life both during treatment and for years after for these young patients,” said the study’s senior author Christine Hill-Kayser, MD, chief of the Pediatric Radiation Oncology Service at Penn and an attending physician at CHOP. CHOP cancer patients who need radiation therapy are treated at Penn, including proton therapy through the Roberts Proton Therapy Center.

Jennifer Vogel, MD, a resident in Radiation Oncology at Penn, is the study’s lead author.

Researchers looked at 69 pediatric head and neck cancer patients treated with PBT at Penn and CHOP between 2010 and 2016. Thirty-five (50 percent) of those patients had rhabdomyosarcoma, a cancer of the cells that make up skeletal muscles. Ten (7 percent) were treated for Ewing sarcoma, a cancer most commonly found in the bone or soft tissue. The other 24 were treated for a variety of other cancers affecting the head and neck regions.

One year after treatment, 93 percent of patients were still alive, and 92 percent did not experience recurrence at their primary disease site.

Toxicities, or side effects, are measured on a scale from 1 to 5 with 5 being the most severe. In this study, no patients were above grade 3, and the most severe toxicities at that level were mucositis (4 percent), loss of appetite (22 percent), and difficulty swallowing (7 percent).

“Different disease sites required different dosage levels, and we specifically found the severity of muscositis was associated with higher doses of radiation,” Vogel said.

Those numbers are still well below what is typically associated with photon radiation. In rhabdomyosarcoma, for example, 46 percent of patients historically report grade 3 or 4 mucositis.

“These data show proton therapy is not only effective, it is also more tolerable for patients,” Hill-Kayser said. “This study shows this treatment is safe and offers practice guidelines for delivering head and neck proton therapy in the pediatric population.”

Researchers say they plan to follow up with these patients to evaluate long-term disease control and late-developing toxicity.

German research advances in cancer and blood disorders reported in human gene therapy

Virotherapy capable of destroying tumor cells and activating anti-tumor immune reactions, and the use of engineered hematopoietic stem cells (HSCs) to deliver replacement genes that have the potential to cure blood diseases are among the key areas of gene therapy being advanced by German researchers and highlighted in a special issue of Human Gene Therapy, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The issue is available free on the Human Gene Therapy website.

The special focus issue entitled “German Gene Therapy Research — Part 1 ,” was developed by Guest Editors Christof von Kalle, MD, Boris Fehse, PhD, and Hildegard Büning, PhD. Dr. Büning, Hannover Medical School, is Editor of Human Gene Therapy Methods and serves as Chair of the 25th Anniversary ESGCT Congress, October 17-20, in Berlin.

In the special issue, Guy Ungerechts and Christine Engeland led a team of colleagues from Germany and Luxembourg in coauthoring the review article entitled “Virotherapy Research in Germany: From Engineering to Translation.” The researchers present the latest preclinical and clinical research activities to engineer oncolytic viruses, which selectively infect tumor cells, for use in tumor-targeted gene therapy. They discuss the different types of virus platforms being investigated–including adenovirus, arenavirus, measles vaccine virus, parvovirus, and vaccinia virus — and the potential to take advantage of the immunotherapeutic properties of oncolytic viruses and of their use in combination with other types of pharmaco-, radio-, and immunotherapy.

In the review article “Promises and Challenges in Hematopoietic Stem Cell Gene Therapy,” Saskia Kohlscheen, Halvard Bonig, and Ute Modlich, Paul-Ehrlich-Institute (Langen), Goethe University (Frankfurt), German Red Cross Blood Service Baden-Württemberg-Hessen (Frankfurt), Germany, and University of Washington, Seattle, describe the state-of-the-art in HSC-directed gene therapy, including viral vector delivery systems, transduction of HSCs, and protocols prior to HSC transplantation. The researchers discuss the main targets for this innovative approach, focusing on immunodeficiencies and inborn errors of metabolism, what has been learned to date from the limiting clinical studies performed, and how best to move forward to overcome the challenges the field still faces.

“The rapid pace of innovation among gene and cell therapy researchers in Germany is striking and significant,” says Editor-in-Chief Terence R. Flotte, MD, Celia and Isaac Haidak Professor of Medical Education and Dean, Provost, and Executive Deputy Chancellor, University of Massachusetts Medical School, Worcester, MA. “We are very proud to reflect the impact of German gene therapy science in this special issue of Human Gene Therapy.”

Moffitt Researchers Discover New Targets for Approved Cancer Drug

New study shows ALK inhibitor ceritinib may have the ability to be used for more than ALK-rearranged non-small cell lung cancer

Developing new drugs to treat cancer can be a painstaking process taking over a decade from start to Food and Drug Administration approval. Scientists are trying to develop innovative strategies to identify and test new drugs quicker and more efficiently. A team of researchers at Moffitt Cancer Center used cellular drug screening, functional proteomics and computer-based modeling to determine whether drugs with well-known targets may be repurposed for use against other biological targets. They found that an FDA approved drug for non-small cell lung cancer called ceritinib has anti-cancer activity against previously unknown targets. Their results were published today in the journal, Nature Chemical Biology.

For the past 20 years, there has been an emphasis on targeted cancer therapy – targeting a specific driver of cancer development to minimize side effects typically seen with chemotherapy. This personalized approach has been successful in certain types of cancer that are primarily driven by a single DNA alteration, such as found in chronic myeloid leukemia. However, the majority of cancers are not caused by a single mutation; rather, cancer is more commonly caused by a large network of mutations and alterations. Some researchers, including those from Moffitt, are beginning to rethink the targeted approach to cancer therapy. They believe that developing drugs that act on multiple targets, called a polypharmacology approach, may more effectively treat those cancers that have a network of alterations.

In order to identify drugs that act on multiple targets, Moffitt researchers screened 240 drugs that are either FDA approved or in clinical development. They noticed that the drug ceritinib acts differently than other drugs in its class. Ceritinib targets a protein called ALK, and is approved to treat patients with ALK-rearranged metastatic non-small cell lung cancer. Their research found that ceritinib also inhibits the growth of lung cancer cells that do not have genetic alterations in the ALK gene.

After an extensive set of experiments to learn how ceritinib worked in cells without ALK rearrangements, they discovered the drug inhibits several other previously unknown targets, and that these signals converge onto a protein known to be responsible for causing drug resistance to paclitaxel. Importantly, the researchers showed that ceritinib combined with paclitaxel was more effective than either agent alone at reducing cell viability.

These findings suggest that ceritinib together with paclitaxel may be effective against other cancers that do not have ALK rearrangements, and that this drug combination may be used to target a network of changes in cancer.

“The results also demonstrate the benefits of using a combined screening, proteomics and computer-based modeling approach to identify drugs that act on multiple targets and to determine how they function,” said study lead author Uwe Rix, Ph.D., assistant member of the Drug Discovery Program at Moffitt. “In the future, this strategy may facilitate further drug repurposing efforts and lead to an increase in new therapy options for patients with difficult-to-treat diseases.”

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.

Bariatric surgery lowers cancer risk for severely obese patients

Severely obese patients who undergo bariatric surgery lower their risk of developing cancer by at least a third, according to a University of Cincinnati (UC) College of Medicine researcher leading a large retrospective cohort study of patients in the western United States.

“We found having bariatric surgery is associated with a reduced risk of cancer, especially obesity-associated cancers including postmenopausal breast cancer, endometrial cancer, pancreatic cancer and colon cancer,” explains Daniel Schauer, MD, associate professor in the UC Division of General Internal Medicine and lead researcher. “What’s surprising is how great the risk of cancer was reduced.”

The findings were recently published online in the Annals of Surgery.

The study reviewed medical data of 22,198 individuals who had bariatric surgery and 66,427 nonsurgical patients between 2005 and 2012 with follow-up through 2014. It pulled data from large integrated health insurance and health care delivery systems from five study sites operated by Kaiser Permanente–Southern California, Northern California, Oregon, Colorado and Washington.

More than 80 percent of patients in the study were women.

Patients undergoing bariatric surgery had a 33 percent lower risk of developing any cancer during follow-up, according to the published findings. Schauer says the benefit is greatest among obesity-associated cancers. The risk of postmenopausal breast cancer dropped by 42 percent and while the risk for endometrial cancer dropped 50 percent in severely obese patients. The risk of colon cancer dropped 41 percent while the risk of pancreatic cancer was lowered by 54 percent.

“Cancer risks for postmenopausal breast cancer and endometrial cancer are closely related to estrogen levels,” says Schauer. “Having weight loss surgery reduces estrogen level.”

Bariatric surgery helps reduce the risk of diabetes and insulin levels which may be a risk factor for pancreatic cancer, while the mechanisms for colon cancer are more complicated, says Schauer.

“I think considering cancer risk is one small piece of the puzzle when considering bariatric surgery, but there are many factors to consider. Reductions in diabetes, hypertension and improvements in survival and quality of life are reason enough,” says Schauer. “The study provides an additional reason to consider bariatric surgery.”

The study found no significant association between bariatric surgery and cancer risk among men. Schauer says that may be because the vast majority of study patients are female and at least two of the cancers most impacted by bariatric surgery, postmenopausal breast cancer and endometrial cancer, affect women only.

Multivariable Cox proportional-hazards models were used to examine the incidence of cancer up to 10 years after bariatric surgery compared to the matched nonsurgical patients. After a mean follow-up of 3.5 years, researchers identified 2,543 incident cancers.

About 15 million adults in the United States suffer from severe obesity, which is defined as having a body mass index of greater than 35 kg/m2. Obesity and cancer are closely linked. Obesity is associated with up to 40 percent of all cancers diagnosed in the United States, says Schauer.

Tests with topical treatment strategy for fighting skin cancer yield positive results

Researchers at the University of São Paulo (USP), in Brazil, are testing a technique in mice that combines low-intensity electric current with a formulation containing nanoencapsulated chemotherapy to treat skin cancer.

Applying a low-intensity unidirectional current is one of the ways to ensure that chemical substances penetrate the skin, pushed into the bloodstream through the electric field using a technique known as iontophoresis.

According to preliminary results of the study, cancer-induced mice which received the formulation combined with iontophoresis presented a significantly greater reduction in the size of the tumor than those that received it through injection.

“One of the challenges involved in this type of topical treatment is ensuring that the drug penetrates the stratum corneum – the outermost layer of the epidermis, composed mainly of dead cells. It is an important tissue barrier against the entry of microorganisms, but it also makes it more difficult for medicines to penetrate,” explained Renata Fonseca Vianna Lopez, who supervises the Thematic Project supported by the São Paulo Research Foundation – FAPESP and is also a at the School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP-USP).

In the case of skin cancer, however, the intent is not that the drug penetrates the tissue to get into the bloodstream, but rather that it becomes concentrated in the area below the stratum corneum that requires treatment. This is the reason why, in the study led by Lopez, she chose to place the chemotherapeutic agent inside nanoparticles.

In vivo tests

Using mice, the researchers induced the formation of a tumor associated with one of the most common types of skin cancer – squamous cell carcinoma – through a subcutaneous injection of human tumor cells that overexpress the epidermal growth factor receptor (EGFR). Lopez explained that the presence of this protein causes the tumor to become more aggressive.

The treatment was conducted using a formulation containing chemotherapy agent 5-fluorouracil encapsulated in a nanoparticle (liposome) that functions as an anti-EGFR antibody. The malignant cells are able to capture a larger quantity of the drug encapsulated in these liposomes.

One group of rodents received the tumor formulation through subcutaneous injections and another group received it through topical application combined with iontophoresis. Lopez compared both methods and thus assessed:

“In addition to reducing the size of the tumor, the topical treatment left the tumor less aggressive. We believe that this method combined with iontophoresis allows the drug to be dispersed over the entire area of the tumor, whereas the subcutaneous application causes it to be concentrated in a single location,” Lopez noted.

Versatile technique

In another study, Lopez’ group used a stiffer type of polymeric nanoparticle, one containing the anti-inflammatory dexamethasone associated with iontophoresis for the treatment of uveitis – an inflammation of the eye tissue. The results, published in 2015 in the Journal of Controlled Release, is the outcome of the doctoral thesis of Joel Gonçalves Souza, winner of the 2015 Capes Thesis Award in Pharmacy.

“When we apply the medicine directly to the eye, it is quickly eliminated through the defense mechanisms, such as tears. Increased penetration and better results are obtained by using the application method combined with iontophoresis,” Lopez said.

Currently, in dissertation research by Camila Lemos, the group plans to test a method that uses iontophoresis in the treatment of chronic wounds such as those that develop in patients with diabetes.

“In this case, we are not dealing with the stratum corneum barrier. We use iontophoresis to assess its influence on release of the substance of interest in a formulation, and to investigate its effect on the growth of microorganisms,” Lopez explained.

The strategy consists of placing a peptide having anti-inflammatory properties on a film made of fibers extracted from the cocoon of a silkworm (fibroin). The film is placed on the wound as a dressing, to which an electric current is then applied.

“When we placed the peptide directly on the wound, it degraded very quickly. When placed on the film, however, release occurs in a slower and more sustained way. Iontophoresis allows a larger amount of the peptide to be released from the film at the start of treatment to accelerate healing,” the researcher explained.

Lopez went on to say that preliminary results suggest that iontophoresis also stops the proliferation of some types of microorganisms (particularly gram-positive bacteria) that could aggravate wounds.

Blood Test for HPV May Help Predict Risk in Cancer Patients

A blood test for the human papillomavirus, or HPV, may help researchers forecast whether patients with throat cancer linked to the sexually transmitted virus will respond to treatment, according to preliminary findings from the University of North Carolina Lineberger Comprehensive Cancer Center.

HPV can cause oropharyngeal cancer, which is a cancer of the throat behind the mouth, including the base of the tongue and tonsils. Studies have shown that patients with HPV-positive oropharyngeal cancer have better outcomes than patients whose cancer is not linked to the virus.

Preliminary findings presented at this year’s American Society for Radiation Oncology Annual Meeting suggest a genetic test for HPV16 in the blood could be useful to help assess risk for patients, and could help identify patients suitable for lower treatment doses.

“Our work on this blood test is ongoing, but we are optimistic that ‘liquid biopsy’ tests such as ours may be useful in the personalization of therapy for many patients with HPV-associated oropharyngeal cancer,” said the study’s senior author Gaorav P. Gupta, MD, PhD, UNC Lineberger member and assistant professor in the UNC School of Medicine Department of Radiation Oncology.

To avoid over-treating patients and to spare them from toxic treatment side effects, UNC Lineberger’s Bhisham Chera, MD, an associate professor in the radiation oncology department, led studies testing whether favorable-risk patients with HPV-positive oropharyngeal cancer can be treated successfully with lower doses of radiation and chemotherapy. A phase II clinical trial using this de-intensified regimen have shown “excellent” cancer control, Chera said.

The researchers used a number of selection criteria to identify patients who can benefit from lower-doses: patients had to be positive for HPV, and they had to have smoked fewer than 10 pack years. Chera said this system is not perfect, however. The researchers have seen cancer recur in non-smoking patients as well as “excellent” cancer control in longtime smokers.

“This has led us to question whether we can get better prognostication with other biomarkers,” Chera said.

They developed a test that can detect HPV16 circulating in the blood, and found that circulating HPV16 DNA was detectable using the test in the majority of a group of 47 favorable-risk oropharyngeal cancer patients.

In a finding that seems counterintuitive, they discovered that very low or undetectable HPV16 pretreatment levels in their blood actually had higher risk of persistent or recurrent disease for chemotherapy and radiation treatment. In contrast, patients with high pretreatment levels of HPV16 in their blood had 100 percent disease control.

They hypothesized that, potentially, the patients with undetectable/low pre-treatment HPV16 levels in the blood may have different, more radiation/chemotherapy resistant cancers.

“Our current theory is that these patients with low or undetectable levels of HPV16 have a different genetic makeup—one that is perhaps less driven purely by HPV, and thus potentially less sensitive to chemotherapy and radiation,” Gupta said. “We are performing next generation sequencing on these patients to search for additional genetic markers that may give us a clue regarding why they have a worse prognosis.”

They also identified a subset of patients who rapidly cleared the HPV16 from their blood. Researchers hypothesize that they could use their findings to further stratify patients who may be eligible for lower intensity treatment.

“A tantalizing – and yet currently untested – hypothesis is whether this subset of ultra-low risk patients may be treated with even lower doses of chemoradiotherapy,” Gupta said.

By Decoding How HPV Causes Cancer, Researchers Find a New Potential Treatment Strategy

A study that teases apart the biological mechanisms by which human papillomaviruses (HPV) cause cancer has found what researchers at Georgetown University Medical Center say is a new strategy that might provide targeted treatment for these cancers.

HPVs are responsible for the majority of cervical cancer and a substantial portion of head and neck and anal cancers, but therapy available to date is surgery and non-specific chemotherapy.

The new study, published Oct. 2 in the journal Oncotarget, found that E6, an oncoprotein produced by the virus, interacts with several other molecules in host cells in a manner that ensures infected cells cannot die. If they are immortal and continue to multiply, cancer develops.

“There is no targeted treatment now for these cancers since German virologist Harald zur Hausen, PhD, discovered in 1983 that HPV can cause cervical cancer. Recently, the numbers of HPV-linked head and neck cancers have increased in the U.S. Now we have a chance to develop and test a very specific, potentially less toxic way to stop these cancers,” says the study’s lead author, Xuefeng Liu, MD, associate professor of pathology at Georgetown University Medical Center.  Liu is director of Telomeres and Cell Immortalization for the medical center’s Center for Cell Reprogramming.

Liu and his team have previously found that the HPV E6 oncoprotein interferes with the well-known p53 tumor suppressor to increase telomerase activity that extends the life span of infected cells. A telomerase is a protein that allows a cell to divide indefinitely when it would have stopped after a certain number of divisions.

In this study, researchers found that E6 also interacts with myc, a protein produced by the Myc gene, which controls gene expression in all healthy cells. They concluded that telomerase activity is dependent on E6-myc proteins hooking on to each other.

This means, says Liu, that designing a small molecule that stops E6 from joining up with myc should shut down persistent activation of telomerase. A small molecule could bind to E6 in the same spot that myc would, or bind on to myc in the same spot that E6 would, thus preventing an E6-myc complex.

“This small molecule would not be toxic to all normal cells or, importantly, to master stem cells, because myc would not be affected,” says Liu. “It could be a unique treatment, targeted specifically to HPV cancers.”

Georgetown researchers are now working on a prototype chemical to interfere with E6/Myc binding.

Editing genes one by one throughout colorectal cancer cell genome uncovers new drug target

Cancers driven by mutations in the KRAS gene are among the most deadly. For decades, researchers have tried unsuccessfully to directly target mutant KRAS proteins as a means to treat tumors. Instead of targeting mutant KRAS itself, researchers at University of California San Diego School of Medicine are now looking for other genes or molecules that, when inhibited, kill cancer cells only when KRAS is also mutated.

The team used the CRISPR-Cas9 gene editing technique to systematically inactivate every gene in the genome of human colorectal cancer cells with and without mutant KRAS. They found that growth of KRAS-mutant colorectal cancer cells in mice was reduced by approximately 50 percent when two genes that encode metabolic enzymes — NADK and KHK — were also inactivated.

The study, published September 27 in Cancer Research, provides potential new drug targets for KRAS-driven cancers.

“We did not get these same results with cancer cells grown in the lab — the growth inhibition we saw when the NADK and KHK genes were inactivated only occurs in tumors in a mammalian system, in a more realistic microenvironment where the tumor has to survive,” said senior author Tariq Rana, PhD, professor of pediatrics at UC San Diego School of Medicine and Moores Cancer Center. “That suggests that the metabolic dependencies of tumor cells growing in a laboratory dish may differ dramatically compared to the same cells growing in a living system, underscoring potential limitations of standard laboratory-based cancer cell growth tests.”

Approximately 20 to 30 percent of all human cancers have mutations in the KRAS gene. KRAS mutations occur in many of the most lethal and most difficult to treat cancers, including lung, pancreatic and colorectal cancer. KRAS mutant cancer cells are able to rewire their metabolism in a way that gives them a growth advantage compared to normal cells.

Rana’s approach to treating KRAS-driven cancers — inhibiting other genes or molecules in addition to KRAS — is called “synthetic lethality” because the intervention is only lethal to the mutated cells. In a previous study, Rana’s team used a library of microRNAs, small pieces of genetic material, to systematically block protein production and look for those inhibitions that are synthetic lethal in combination with KRAS mutations.

In their latest study, Rana’s team used CRISPR-Cas9 to systematically inactivate genes in two human colorectal cancer cell lines — one with normal KRAS and one with a mutant KRAS. They then tested the ability of each of these cell lines to grow as tumors in mice. They found that inactivating two metabolic enzymes, NADK and KHK, reduced the growth of KRAS-mutant tumors by approximately 50 percent, but had no effect on normal KRAS tumors. They also blocked these same enzymes with commercially available small molecule inhibitors and saw significant reduction in tumor growth in mice only in tumor cells with mutant KRAS.

Rana and team also identified several new genes that, when inactivated, had the opposite effect — they increased KRAS-mutant tumor growth, but not the growth of normal KRAS tumors. These types of genes are known as “tumor suppressors” because they normally keep cancer cell growth in check.

“One of the most surprising findings from our study is how performing this type of genetic screen directly in a mammalian microenvironment revealed not only new synthetic lethal interactions, but also new tumor suppressor genes that are dependent on KRAS mutations,” said first author Edwin Yau, MD, PhD, a hematology/oncology and Cancer Therapeutics Training Program fellow in Rana’s lab.

One of these new tumor suppressor genes encodes INO80C, a large multi-subunit protein that, among other things, stabilizes the genome. Rana, Yau and colleagues are now taking steps to carry their findings forward, with the ultimate goal of better understanding how KRAS-mutant cancers develop and translating these insights into developing new therapies to stop them.

Drug Combo Gangs Up to Take on Triple-Negative Breast Cancer

Researchers find novel combination disrupts multiple factors in aggressive type of cancer

In the hunt for novel treatments against an aggressive form of breast cancer, researchers combined a new protein inhibitor with a chemotherapy drug to create a powerful combination that resulted in cancer cell death.

Triple-negative breast cancer is a subtype that does not express hormone receptor or HER2. It occurs in approximately 15 percent of patients with breast cancer. This subtype tends to be more aggressive and targeted therapeutic treatment options are lacking.

In this work, the drugs studied were each tested separately in triple-negative breast cancer cell lines and in mice with the disease. The researchers then implemented the treatments in combination. The combination produced a synergistic effect that was more effective than either drug alone. The cancer cells treated with the drug combination were less likely to multiply or spread in cell culture and were less viable in an animal model.

Preliminary data had shown that inhibiting proteins called cyclin dependent kinases, or CDKs, might be effective against triple negative breast cancer. In this study, researchers tested a pharmaceutical grade CDK inhibitor called CYC065. Additionally, researchers used the chemotherapy drug eribulin, which had shown promise in prior clinical trials for the treatment of triple-negative breast cancer.

“In this pre-clinical study, we showed that the combination of CYC065 and eribulin had a synergistic effect against the growth and progression of triple-negative breast cancer. New therapeutic targets and treatment strategies are crucial to improve outcomes for women with this aggressive breast cancer subtype,” says study author Jacqueline S. Jeruss, M.D., Ph.D., director of the Breast Care Center at the University of Michigan Comprehensive Cancer Center.

From the early days of her career, Jeruss was interested in how signaling pathway alterations could impact the development of breast cancer. What makes a mammary cell change to allow for lactation but then regress when that function is no longer needed? What orchestrates cell regulation to allow for such carefully mediated physiologic changes? And what processes occur over time that cause the cellular deregulation leading to cancer development in certain patients, but not in others?

Her work led her to the implementation of CDK inhibitors for the treatment of triple negative breast cancer. She found that these drugs could help to block the harmful impact of overexpression of cancer promoting cyclin E/CDKs, proteins that were inhibiting the tumor suppressant action of the TGF-beta/SMAD3 pathway. CDK inhibitors can block the impact of cyclin E/CDK action, helping to restore the beneficial effects of the TGF-beta/SMAD3 pathway, and thus facilitating cancer cell death.

In the current study, published in Oncotarget, the combination treatment of the CDK inhibitor CYC065 with the chemotherapy eribulin, resulted in less viable triple negative breast cancer cells, smaller tumor colonies, decreased cell migration, and small tumor size in an animal model.

Researchers also identified specific transcription factors that were impacted by CYC065. These processes likely work together to promote cancer cell death.

“We have begun to identify a network of vulnerable and targetable signaling components within the triple negative cancer cells that can be exploited with CDK inhibitor and chemotherapy treatment to promote triple negative breast cancer cell death,” Jeruss says.

The research was done with triple negative breast cancer cells in culture and in an animal model. The next step is for researchers to develop a clinical trial to test the drug combination in patients with triple-negative breast cancer.

Prostaglandin E1 Inhibits Leukemia Stem Cells Targeting leukemia stem cells in combination with standard chemotherapy may improve treatment for chronic myeloid leukemia

Two drugs, already approved for safe use in people, may be able to improve therapy for chronic myeloid leukemia (CML), a blood cancer that affects myeloid cells, according to results from a University of Iowa study in mice.

CML is a relatively common cancer. The American Cancer Society estimates that in 2017 there will be about 8,950 new cases and about 1,080 people will die of the disease.

In its initial, chronic stage, CML is relatively easy to treat. Drugs called tyrosine kinase inhibitors (TKIs) are generally successful at controlling the cancer. However, patients need to continue the expensive treatment for their lifetime. In some cases, even with that treatment, the cancer can progress to a more advanced stage that is no longer controlled.

One reason for this, explains Hai-Hui (Howard) Xue, MD, PhD, UI professor of microbiology and immunology, is that there are two kinds of tumor cells—bulk leukemia cells that can be killed by TKI drugs, and a subset of cells called leukemia stem cells, which are resistant to TKIs and to chemotherapy.

“A successful treatment is expected to kill the bulk leukemia cells and at the same time get rid of the leukemic stem cells. Potentially, that could lead to a cure,” says Xue, who is senior author of the study published in the September issue of the journal Cell Stem Cell as the cover story.

With that goal in mind, Xue and his team joined forces with Chen Zhao, MD, PhD, UI assistant professor of pathology, and used their understanding of CML genetics to look for small molecules or drug compounds that might be able to eradicate the leukemia stem cells.

Focusing on two proteins known as transcription factors, the researchers showed that genetically removing the two transcription factors, Tcf1 and Lef1, in mice is sufficient to prevent leukemia stem cells from persisting. Importantly, this genetic alteration did not affect normal hematopoietic (blood) stem cells.

Next the researchers used an informatics method called connectivity maps to identify drugs or small molecules that can replicate the gene expression pattern that occurs when the two transcription factors are removed. This screening test identified a drug called prostaglandin E1 (PGE1).

The team tested a combination of PGE1 and the TKI drug called imatinib in a mouse model of CML. The mice lived longer than control mice; 30 percent lived longer than 80 days compared to mice treated with only imatinib, all of which died within 60 days.

The team also looked at a different mouse model of CML, where human CML cells were transplanted into an immunocompromised mouse. When the mice received no treatment or were treated with imatinib alone, the human leukemia stem cells propagated and grew to relatively large numbers. In contrast, when the animals were treated with a combination of imatinib and PGE1, those numbers were greatly reduced, and mice did not develop leukemia.

“The results are a pleasant surprise,” says Xue who also is a member of Holden Comprehensive Cancer Center at the UI. “We do these kinds of genetic studies all the time—looking at transcription factors and what they do. This is a good opportunity to connect what we do at the bench to something that could be useful clinically.”

Investigating how the PGE1 works to suppress the leukemia stem cells, the team found that the effect relies on a critical interaction between PGE1 and its receptor EP4. They then tested the effect of a second drug molecule called misoprostol, which also interacts with EP4, and showed that misoprostol also has the ability to combine with TKI and significantly reduce the number of leukemia stem cells.

Both PGE1 and misoprostol are currently approved by the FDA for use in people. PGE1 is an injectable drug that is used to treat erectile dysfunction. Misoprostol is a pill that is used to treat ulcers.

“We would like to be able to test these compounds in a clinical trial,” Xue says. “If we could show that the combination of TKI with PGE1, or misoprostol, can eliminate both the bulk tumor cells and the stem cells that keep the tumor going, that could potentially eliminate the cancer to the point where a patient would no longer need to depend on TKI.”

Halving Radiation Therapy for HPV-Related Throat Cancer Offers Fewer Side Effects and Similar Outcomes, Mayo Study Finds

Mayo Clinic researchers have found that a 50 percent reduction in the intensity and dose of radiation therapy for patients with HPV-related throat cancer reduced side effects with no loss in survival and no decrease in cure rates. Results of a phase II study were presented today at the 59th Annual Meetingof the American Society for Radiation Oncology in San Diego by Daniel Ma, M.D. a radiation oncologist at Mayo Clinic.

“A common approach for treating HPV-related throat cancer is a combination of surgery followed by daily radiation therapy for six to 6½ weeks,” says Dr. Ma. “However, the radiation treatment can cause a high degree of side effects, including altered taste, difficulty swallowing, dry mouth, stiff neck and damage to the jaw bone.”  Dr. Ma says that patients with HPV-related throat cancer tend to be young and, once treated, are likely to live a long time with possibly life-altering side effects from the standard treatment. “The goal of our trial was to see if an aggressive reduction of radiation therapy (two weeks of radiation twice daily) could maintain excellent cure rates, while significantly reducing posttreatment side effects, improving quality of life and lowering treatment costs.”

Researchers followed 80 patients with HPV-related oropharyngeal squamous cell cancer with no evidence of residual disease following surgery and a smoking history of 10 or fewer pack years. That’s the number of years smoking multiplied by the average packs of cigarettes smoked per day.

At two years following the aggressively de-escalated treatment, the rate of tumor control in the oropharynx (throat) and surrounding region was 95 percent. Of the 80 patients in the trial, only three experienced a local cancer recurrence. One patient experienced a regional cancer recurrence. Patient quality of life largely improved or did not change following treatment, except for some dry mouth.

“Patients in our trial had a very dramatic reduction in side effects, compared with standard treatment,” says Dr. Ma. “For example, no patient in our trial needed a feeding tube placed during dose-reduced treatment; whereas, close to a third of patients had feeding tubes placed with traditional radiation therapy doses on other recent clinical trials.” Dr. Ma says the reduction in side effects did not lead to any reduction in cure rate, as survival rates were similar to traditional survival rates for HPV-related throat cancer.