A new HER2 mutation, a clinical trial and a promising diagnostic tool for metastatic breast cancer

There is a group of metastatic breast cancers that has the HER2 gene amplified – the cells have many copies of it – which leads to enhanced activity of the product enzyme, a tyrosine kinase. HER2 has been established as a therapeutic target in breast cancer, and breast cancers in which the HER2 gene is not amplified do not, in general, respond to HER2-directed therapeutic approaches.

A few years ago, when the research teams of Dr. Matthew Ellis and others carried out a molecular characterization of breast cancer tumors, they found a new mutation in HER2 that was different from gene amplification but also resulted in tyrosine kinase being constantly activated.

“In this particular activation mechanism, the cells develop a subtle mutation within the functional part of the HER2 gene that activates the enzyme,” said Ellis, professor and director of the Lester and Sue Smith Breast Center, part of the National Cancer Institute-designated Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine. “The mutation locks the enzyme into an ‘on’ position.”

Ellis and his colleagues developed a preclinical model to study this new HER2 mutation and discovered that the enhanced enzymatic activity could trigger tumor formation. Furthermore, these tumor cells were sensitive to an experimental drug, neratinib. With this information in hand, the researchers took the next step.

“We launched a phase II clinical trial of neratinib in patients with metastatic breast cancer carrying a HER2 mutation,” Ellis said. “Finding patients that are positive for a HER2 mutation required a national collaboration because we had to screen hundreds of patients to identify the 2 to 3 percent that have a tumor driven by a HER2 mutation. The results of the clinical trial were encouraging in that about 30 percent of the 16 patients treated with neratinib had a meaningful clinical response showing significant disease stabilization or regression. Neratinib was well tolerated by most patients.”

“This is the first time we had a reasonable number of patients treated for HER2 mutations in whom we could estimate the response rate.”

The number of patients who could potentially benefit from this new treatment approach is estimated to be in the thousands. The researchers estimate that as many as 200,000 patients are likely to be living with metastatic breast cancer today in the United States. Based on the estimate that the new mutation is present in 2 to 3 percent of cases, the researchers calculated that approximately 4,000 to 6,000 patients with metastatic breast cancer carry a HER2 mutation and are therefore potential candidates for neratinib treatment.

Circulating tumor DNA analysis, a promising diagnostic tool

To identify the patients in this study who carried the new HER2 mutation, the researchers required tissue from the tumor, a biopsy, from which they could extract and sequence the genetic material to determine the presence of the HER2 mutation. This task turned out to be a major challenge because for 20 to 30 percent of the patients the researchers did not have sufficient material to make the diagnosis.

“To assist in our ability to identify patients with HER2 mutation-positive tumors, we conducted circulating tumor DNA analysis,” Ellis said. “The tumor’s DNA is released into the human bloodstream, and we were able to determine the presence of the mutation in blood samples from the patients. Importantly the circulating tumor DNA results were highly concordant with the tumor sequencing results, and they were much easier to determine. Notably, the blood test was sensitive enough that we could use it as a tool to determine eligibility for the clinical trial.”

In addition to bringing to the table a novel treatment for metastatic breast cancer carrying a HER2 mutation, the researchers have tested the value of the circulating tumor DNA as a disease-monitoring marker.

“A circulating tumor DNA-based blood test also could therefore be potentially used to monitor tumor progression and to determine whether patients are responding or not to treatment after just one month of therapy,” Ellis said.

Ellis also is a McNair Scholar at Baylor.

Read all the details of this study, the full list of contributors and their financial support in Clinical Cancer Research.

Clinical Trial Results Marks a Significant Accomplishment for Medicortex Finland

Medicortex Finland Oy, a biotechnology company developing a diagnostic kit for brain injury detection based on a medical breakthrough biomarker, recently completed analyzing the results from the first clinical trial. Medicortex is working towards the validation of a Traumatic Brain Injury (TBI) biomarker and incorporating it into a quick and reliable diagnostic kit that can be easily used by the first responders and healthcare professionals, and by people with no medical profession.

The trial consisted of patients that were hospitalized due to a head injury.  Medicortex collected body fluid samples of 12 patients who had sustained a head injury, and analyzed the presence of the novel biomarker between the patients and healthy control subjects.

“The biodegradation product we are targeting has never been used for TBI indication. The fact that we can readily find it in easily accessible body fluids such as urine and saliva enables us to develop a user-friendly diagnostic kit for TBI detection”, says Dr. Adrian Harel, Chief Executive Officer of Medicortex Finland.

“Collecting and testing human samples in a clinical trial is a significant accomplishment for us, and represents a meaningful step forward in the development of a fast and inexpensive diagnostic kit for head injuries,” added Dr. Harel. “Brain injuries are devastating, leading to mortality if not diagnosed. The opportunity to develop the first portable non-invasive kit to detect head injuries and concussion is so desperately needed,” added Harel.

Dr. Marten Kvist, Medical Director of Medicortex, says “We are excited of the clinical results which confirm the diagnostic potential of the unique biomarker, it will be further developed into a diagnostic aid for first responders and paramedics, it will help prioritize evacuation and reframe from administration of contraindicated medications.”

The clinical trial was supported and funded in part by Tekes (the Finnish Funding Agency for Innovation). Medicortex is currently raising money for the next step clinical development of the brain injury test. The planned multicenter clinical study including up to 160 study subjects will prove the validity of the new biomarker test for TBI diagnostics.

The general public can help contribute in the development of MediCortex’s diagnostic kit via a crowdfunding campaign at www.invesdor.com/medicortex  Medicortex is issuing shares with the goal of raising capital to match funds the firm has already applied via Tekes.

Medicortex Finland Oy (http://www.medicortex.fi) is a biotechnology company dedicated to improving the diagnostics and treatment of Traumatic Brain Injury (TBI). Its current focus is to develop biomarker diagnostics that evaluate the extent and severity of TBI. Once the company completes this test its next goal will be to develop an innovative drug to halt the progression of brain injury.

Liver Cancer Drug May Treat NASH, a Disease Projected to Reach Epidemic Proportions

There is no U.S. FDA approved therapy on the market today for Nonalcoholic steatohepatitis (NASH), a chronic liver disease found in adults and children. Between 5.6 and 8.4 million Americans are living with NASH today and this number is expected to jump to 25 million by 2025, driven by rising obesity rates. NAFLD, the liver disease which is a precursor to NASH, afflicts an estimated 30 million people today.

These numbers are astounding, considering the fact that diabetes is widely considered an epidemic because it impacts 29 million Americans. NAFLD and NASH can lead to cirrhosis, and in later stages, to liver cancer and liver failure.

Israel based Can-Fite BioPharma’s CF102, a drug currently in a Phase 2 trial treating hepatocellular carcinoma (HCC), the most common form of liver disease, is headed into clinical trials for the treatment of NAFLD/NASH. While about 40,000 Americans are diagnosed with liver cancer today, this number may increase with the rising incidence of NASH.

Several other companies are developing potential treatments for NAFLD and NASH. As these drugs come to market, Deutsche Bank projects their annual sales to be in the $35 – $40 billion range by 2025. The CEO of Allergan, Brent Saunders, one of the companies developing NAFLD/NASH drugs described the situation, “With the increasing rates of diabetes, obesity and other metabolic conditions in the U.S. and in developed nations globally, NASH is set to become one of the next epidemic-level chronic diseases we face as a society. It is important that we invest in new treatments today so that healthcare systems, providers and patients have treatment options to face this challenge in the coming years.”

CF102 is a small orally bioavailable drug that binds with high affinity and selectivity to the A3 adenosine receptor (A3AR). A3AR is highly expressed in diseased cells whereas low expression is found in normal cells. Preclinical studies have shown CF102’s efficacy in reducing liver fat in NASH models as compared to placebo, improving liver function, and regenerating liver cells.

Can-Fite reported it has submitted the clinical trial protocol for its Phase 2 study of CF102 in the treatment of NAFLD to leading Institutional Review Boards in Israel. Top medical centers in Israel, including Hadassah Medical Center and Rabin Medical Center are expected to participate in the planned study by enrolling and treating patients.

The multicenter, randomized, double-blinded, placebo-controlled, dose-finding study will enroll 60 patients with NAFLD, with or without NASH. The study will have three arms, including two different dosages of CF102 and a placebo, given via oral tablets twice daily. The study’s primary endpoints will be percent change from baseline in liver triglyceride (fat) concentration. Can-Fite’s drugs, based on A3AR, have been studied in over 1,000 patients.

Given the size and scope of the NAFLD/NASH patient population in the U.S. and around the world, healthcare systems can benefit from several different drugs for this indication. A few drugs are in Phase 3 and some others are in Phase 2. Can-Fite’s CF-102 could emerge as a safe and effective choice.

Sac to the future: Cellular vessels predict likelihood of developing dementia

Researchers at University of California San Diego School of Medicine say tiny micro-vesicle structures used by neurons and other cells to transport materials internally or dispose of them externally carry tell-tale proteins that may help to predict the likelihood of mild cognitive impairment (MCI) developing into full-blown Alzheimer’s disease (AD).

The findings, published online this week in the journal Alzheimer’s & Dementia, represent a quicker and less invasive way to identify impending cognitive decline and begin treatment before progression to established, irreversible dementia.

“MCI is often a transitional stage between normal aging and dementia,” said senior author Robert A. Rissman, PhD, associate professor in the Department of Neurosciences at UC San Diego School of Medicine, director of the Biomarker Core for the Alzheimer’s Disease Cooperative Study (ADCS) and director of the Neuropathology Core and Brain Bank for the UC San Diego Shiley-Marcos Alzheimer’s Disease Research Center. “It’s associated with more minor cognitive impairment and carries an increased risk of developing Alzheimer’s dementia.”

MCI patients progress to AD at rates as high as 10 to 15 percent per year, prompting an increased emphasis upon diagnosing MCI early and developing treatments that can delay or prevent conversion to AD. The need is underscored, write the authors, by the fact that clinical trials of treatments for established AD have thus far failed.

While clinically distinguishable from normal aging and AD, MCI remains nonetheless a complex condition with many and varied causes. “That has prompted great interest in pinpointing underlying biomarkers that can predict the conversion from MCI to AD dementia,” said Rissman. “Finding such biomarkers would also identify persons most likely to be responsive to preventive treatments.”

Currently, the accepted methods for diagnosing preclinical AD patients is to detect protein biomarkers found in cerebrospinal fluid (CSF), in combination with advanced neuroimaging and neuropsychological testing. But CSF sampling involves an invasive, often painful, process. Neuroimaging is expensive. Neuropsychological testing is time-consuming and can often vary from visit to visit.

The new method described in the Alzheimer’s & Dementia study evaluated the potential of exosomes – extremely small vesicles or sacs found in most cell types, including neurons. Exosomes are thought to move materials inside cells and are used to dump cellular trash into the bloodstream for disposal. In the case of disease, Rissman’s group predicted that neuronal derived exosomes (NDEs) would carry damaged or excess proteins and metabolites out of brain cells, among them amyloid and tau biomarker proteins that are strongly associated with AD.

The researchers harvested NDEs from human blood plasma of 60 patients who participated in an 18-month ADCS clinical trial that enrolled MCI patients only. Some of these MCI patients converted to AD over the course of the study and some did not. Rissman’s lab also gathered samples from control patients and samples from known AD patients. They enriched the NDE content of those originating from neurons. The samples represented patients with normal cognitive function, diagnoses of stable MCI and stable AD and patients who had recently transitioned from MCI to AD.

After characterizing NDEs by size, shape and concentration, the researchers compared that data with the different patient cohorts. They found that NDEs carried targeted biomarker proteins, which have previously been found to predict development of AD up to 10 years before onset of clinical symptoms, and correctly distinguished 100 percent of patients with AD from normal cohorts.

Moreover, the researchers showed for the first time that plasma NDEs from AD and MCI patients may propagate tau tangles in the brains of normal mice similar to what is seen in human AD brains. The fact that these NDEs could induce pathological-like structures in “naïve” mice (animals not previously subjected to experiments) suggests that the contents of NDEs are bioactive, said Rissman. It also suggests that released NDEs can be taken up by cells, raising the possibility of NDEs potential for drug delivery.

The development of blood-based biomarkers for AD (and other neurodegenerative diseases) diagnostics could significantly improve the effectiveness and reliability of patient care and future research, said the authors, who encouraged further studies to refine and validate the approach.

Four NCI Cancer Centers Announce Landmark Research Consortium and Collaborations with Celgene

The Abramson Cancer Center at the University of Pennsylvania, The Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai announced the establishment of a research consortium focused on accelerating the discovery and development of novel cancer therapeutics and diagnostics for the benefit of patients.

The consortium aligns four major academic institutions in a unified partnership with the shared goal of creating high-impact research programs to discover new treatments for cancer. The magnitude of the multi-institutional consortium and agreements between Celgene Corporation (NASDAQ: CELG) and each institution will support the rapid delivery of disease-altering programs to the clinic that may ultimately benefit cancer patients, global healthcare systems and society.
Subsequent to establishing the consortium, Celgene entered into four public-private collaboration agreements in which it paid a total of $50 million, $12.5 million to each institution, for the option to enter into future agreements to develop and commercialize novel cancer therapeutics arising from the consortium’s efforts. Over the next ten years the institutions intend to present multiple high-impact research programs to Celgene with the goal of developing new life-saving therapeutics. Subject to Celgene’s decision to opt-in and license the resulting technologies, each program has the potential to be valued at hundreds of millions of dollars.
The four cancer center directors, Steven Burakoff, M.D., of the Icahn School of Medicine at Mount Sinai, Stephen G. Emerson, M.D., Ph.D., of Columbia University, William Nelson, M.D., Ph.D., of Johns Hopkins University and Chi Van Dang, M.D., Ph.D., of the University of Pennsylvania, said in a shared statement, “The active and coordinated engagement, creative thinking and unique perspectives and expertise of each institution have made this collaboration a reality. Our shared vision and unified approach to biomedical research, discovery and development, combined with Celgene’s vast research, development and global commercial expertise, will enable us to accelerate the development and delivery of next-generation cancer therapies to patients worldwide.”

In addition to the benefits of long-standing professional relationships among the four cancer center directors, the depth and breadth of the institutions’ combined research and clinical infrastructures provide an exceptional foundation upon which to build this transformative collaboration. The four institutions collectively care for more than 30,000 new cancer patients each year, and have nearly 800 faculty members who are active in basic and clinical research, and clinical care.

“This is a paradigm-shifting collaboration that further strengthens our innovative ecosystem,” said Bob Hugin, Executive Chairman of Celgene Corporation. “We remain firmly committed to driving critical advances in cancer and believe the tremendous expertise of our collaboration partner institutions will be invaluable in identifying new therapies for cancer patients.”
The four consortium members are among the 69 institutions designated as Cancer Centers by the National Cancer Institute (NCI). These 69 institutions serve as the backbone of NCI’s research in the war against cancer.
The Cancer Trust, a non-profit organization, brought together the four institutions, thereby establishing the multi-institutional research consortium. T.R. Winston & Company, LLC served as the strategic advisor to The Cancer Trust and facilitated negotiations among The Cancer Trust, the institutions and Celgene. The commercialization offices of the four institutions, Columbia Technology Ventures, Johns Hopkins Technology Ventures, Mount Sinai Innovation Partners and the Penn Center for Innovation, subsequently collaborated with Celgene to accelerate this effort to discover and develop new therapies for the treatment of cancer.

“We are extremely proud of what we’ve collectively accomplished through establishing this collaboration and aligning all participants,” said Erik Lium, Ph.D., Senior Vice President of Mount Sinai Innovation Partners. “We look forward to continuing to work closely with one another, our colleagues in research and clinical care, and now with Celgene to advance the discovery of new therapies that will dramatically improve the lives of patients worldwide.”

No symptoms, but could there be cancer? Our chemosensor will detect it!

Many cancers could be successfully treated if the patient consulted the doctor sufficiently early. But how can a developing cancer be detected if it doesn’t give rise to any symptoms? In the near future, suitably early diagnosis could be provided by simple and cheap chemical sensors – thanks to special recognizing polymer films developed at the Institute of Physical Chemistry of the Polish Academy of Sciences in Warsaw.

These days, cancer is no longer a death sentence for the patient. However, the best chances of recovery are when the correct treatment is undertaken at an early stage of the disease. This is where the trouble starts, because many tumours develop over a long period without any symptoms. One solution to this problem could be diagnostic tests available to everyone that could be performed by people themselves and on a relatively regular basis. A step bringing us closer to this sort of personalized medical diagnosis and cancer prophylaxis is the chemical sensor devised and fabricated by Prof. Wlodzimierz Kutner’s group from the Institute of Physical Chemistry of the Polish Academy of Sciences (IPC PAS) in Warsaw using a grant from the National Science Centre, in collaboration with the team of Prof. Francis D’Souza of the University of North Texas in Denton TX, USA.

The most important element of the chemosensor devised at the IPC PAS is a thin film of the polymer that detects molecules of neopterin. Neopterin – in chemical terminology known as 2-amino-6-(1,2,3-trihydroxypropyl)-1H-pteridin-4-one) – is an aromatic compound present in human body fluids, such as serum, urine, and cerebrospinal fluid. Produced by the immune system, it is regarded as a universal marker in medical diagnosis. The concentration of this biomarker rises significantly particularly in the case of certain neoplastic diseases, e.g., malignant lymphoma, although elevated levels of neopterin are also seen in some viral and bacterial infections, as well as in diseases of parasitic aetiology. In turn, in transplant patients, increased levels of neopterin signal probable rejection.

“How can we detect the presence of neopterin? A reasonable approach is to use special recognizing materials for this purpose, prepared by molecular imprinting. This technique involves ‘stamping out’ molecules of the desired compound – their shape, but also at least some of the chemical characteristics – in a carefully designed polymer,” explains Dr. Piyush Sindhu Sharma (IPC PAS), the lead author of an article published in the Biosensors and Bioelectronics journal.

During the preparation of the polymer film, molecules of the substance being detected – in this case neopterin – are in a working solution in which their binding sites have to link with recognizing sites of so-called functional monomers. In turn, these monomers should be able to form connections with another monomer, a cross-linking agent which together, after polymerization, form a rigid support structure of the polymer. Next, the molecules of the compound used as a template are washed out from the structure. The result is a durable polymer with molecular cavities of a shape and chemical properties ensuring the capture of molecules of the desired compound from its surroundings.

The basic difficulty in molecular imprinting is the selection of the appropriate functional and cross-linking monomers as well as solvents, their proportions and reaction conditions. PhD student Agnieszka Wojnarowicz (IPC PAS) explains: “With the aid of quantum-chemical calculations, we first check whether there is bonding between our template molecule and selected functional monomers, and whether they will be stable in the solvent used. We also check whether the molecular cavities formed are sufficiently selective, i.e., whether they will primarily capture the molecules we are detecting, and not any that are similar to them. When the calculation results confirm our expectations, that is when we proceed to their experimental confirmation.”

At the IPC PAS a recognizing polymer film with molecular cavities from neopterin has been produced on the surface of an electrode. After immersion in artificial blood serum spiked with neopterin, the film on the electrode captured molecules of the latter, thus leading to a decrease in electrical potential in the connected measuring system. The tests showed that the molecular cavities of the polymer were almost entirely filled with molecules of neopterin despite the presence of molecules of similar structure and properties. This result means that the probability of false positive detection (detecting the presence of neopterin in body fluids not containing it) is negligibly small. The new chemical sensor therefore mainly reacts to what it should react to – and nothing else.

“At present, our chemosensor is a piece of laboratory equipment. However, the production of its key element, that is, the recognizing polymer film, does not pose major problems, and the electronics responsible for electrical measurements can easily be miniaturized. There is nothing standing in the way of building simple and reliable diagnostic equipment, based on our development, in just a few years’ time, which would be affordable not only for medical institutions and doctors’ surgeries, but also for the public in general,” predicts Prof. Kutner (IPC PAS).

New Technology Is Life-Saving Voice for Premature or Critically Ill Infants

A new technology in the Neonatal Intensive Care Unit (NICU) at UC San Diego Health is able to predict the risk of life-threatening infections up to 24 hours before they appear in severely premature or critically ill infants. Infection is the leading cause of death in this fragile patient population.

The Heart Rate Observation system, or HeRO, is an innovative monitoring technology that uses an algorithm to detect slight changes in a baby’s heartbeat that could be an early sign of a major infection, like sepsis — a bacterial infection that is highly dangerous to babies born three pounds or less.

“The challenge with diagnosing sepsis is a lot of symptoms for the early stages of the infection are subtle and nonspecific,” said Erika Fernandez, MD, director of the NICU at UC San Diego Health. “With the HeRO technology, we can detect symptoms of sepsis up to 24 hours before the infection actually happens. This allows us to begin an investigation and intervene with treatment before a baby becomes critically ill.”

UC San Diego Health is the first health care provider in San Diego County to use the technology, which can detect infections in the blood stream and intestines. Historically, physicians and nurses have relied upon their own observations to detect signs of infection. The new system reports vital sign trends much earlier than the human eye or traditional equipment and requires no additional wiring to the baby.

“This state-of-the-art technology lets babies be babies, and mothers can breastfeed without worrying about tangling up or unplugging wires,” said Lawrence Prince, MD, PhD, chief in the Division of Neonatology at UC San Diego Health. “It makes for a much less intimidating experience for families and a highly improved monitoring approach for medical staff.

The HeRO system uses a zero-to-seven surveillance score generated after a heart rate is analyzed, with anything higher than a two considered an alert for possible infection. Prince says the technology is expected to reduce mortality rates in the NICU by 20 percent.

“Physicians and nurses can evaluate a situation much more thoroughly,” said Prince. “When I look at the data on the monitor, I can ask myself, ‘is there something more going on with the patient and do we need to do further testing?’”

Fernandez added that the monitoring system represents part of the next generation of technology to save lives and help achieve the ultimate goal in the NICU: “To provide the highest quality of comprehensive and compassionate care to NICU babies so they can thrive and go home with their families as soon as possible.”