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For the more than 680,000 Americans living with a brain tumor, there is a revolutionary research effort under way at the Cedars-Sinai Precision Medicine Initiative in Brain Cancer in Los Angeles to look at ways of using precision science to tailor personalized treatments for individuals with malignant brain tumors.
Brain Cancer Meets Precision Science
Brain cancer continues to be among the hardest of diseases to treat. Until now, most medical treatments for the most common, aggressive and lethal form of brain cancer, glioblastoma multiforme, which affects more than 138,000 Americans yearly, have been designed for the average patient. Given that every cancer is genetically unique, this “one-size-fits-all” drug treatment has not worked for brain cancer and for most solid cancers. Unfortunately, today’s standard-of-care, which includes surgical removal, radiation therapy, and chemotherapy, has only modest benefits with patients living on average 15 months after diagnosis.
“Precision Medicine, an innovative approach that takes into account individual differences in people’s genes, environments and lifestyles, only works when we apply ‘Precision Science’ to the effort,” notes Dr. Chirag Patil, M.D., Neurosurgeon & Program Director at Cedars-Sinai Medical Center. “If we want to treat cancer more effectively, we need a novel approach to cancer care. In our program, we use tumor genomics and precision science to build a holistic mathematical model of cancer that then can be used to develop new, personalized cancer treatments. Right now, we’re focused on the most common type of brain cancer, but are developing a unique scientific process that could tackle ANY type of cancer.”
This past year, the White House launched the Precision Medicine Initiative to dramatically improve health and treatment through a $215 million investment in the President’s 2016 budget. The Initiative will provide additional impetus to Precision Medicine’s approach to disease prevention and treatment that has already led to powerful new discoveries and several new treatment methods for critical diseases.
Caption: The Cedars-Sinai program uses precision science to build a mathematical virtual brain tumor for testing.
Delivering Personalized Cancer Care Through Big Data And Virtual Simulations
Harnessing the power of big data, Dr. Patil’s program puts a patient’s brain tumor through next-generation genomic sequencing to establish a comprehensive profile of that specific brain cancer. Researchers, in collaboration with Cellworks Inc., a therapeutics design company, use this profile to build a mathematical “virtual“ tumor cell. The simulations are then compared to the real patient tumor cells that have been growing in Dr. Patil’s laboratory. The “real data” from experiments in the lab are used to confirm the virtual tumor model – again, this is customized for each individual patient.
The next step is to run a virtual experiment where all FDA-approved targeted drug combinations are tried on the virtual tumor cell to identify the best drug combination that eradicates the cells for the specific brain tumor. In the final step, researchers expose the patient’s real cancer cells to this unique and personalized drug combination to ensure that it effectively kills the patient’s cancer cells in the laboratory.
Spreading the Word
This effort is not someday in the future but is happening now, and has demonstrated remarkable progress in the last six months. Researchers expect to have data on 30 brain cancer patients from this precision medicine strategy by mid-2016. From this, they will develop an innovative randomized clinical trial, not simply to compare one drug to another, but rather compare this innovative Precision Medicine treatment algorithm to a current standard treatment regimen.
Learn More
For more information on this revolutionary approach, visit www.BrainTumorExpert.com, to learn more about Dr. Patil and his precision science approach to treating brain tumors.
Other related articles published in this Open Access Online Scientific Journal include the following:
2015
The 11th Annual Personalized Medicine Conference, November 18-19, 2015, Joseph B. Martin Conference Center of the Harvard New Research Building at Harvard Medical School
Scientists at the Weizmann Institute may have found the cure for prostate cancer, at least if it is caught in its early stages – via a drug that doctors inject into cancerous cells and treat with infrared laser illumination.
Using a therapy lasting 90 minutes, the drug, called Tookad Soluble, targets and destroys cancerous prostate cells, studies show, allowing patients to check out of the hospital the same day without the debilitating effects of chemical or radiation therapy or the invasive surgery that is usually used to treat this disease.
The drug has been tested in Europe and in several Latin American countries, and is being marketed by Steba Biotech, an Israeli biotech start-up with R&D facilities in Ness Ziona. The drug and its accompanying therapy were developed in the lab of Weizmann Institute professors Yoram Salomon of the Biological Regulation Department and Avigdor Scherz of the Plant and Environmental Sciences Department.
Based on principles of photosynthesis, the drug uses infrared illumination to activate elements that choke off cancer cells, but spares the healthy ones.
The therapy was recently approved for marketing in Mexico, after a two-year Phase III clinical trial in which 80 patients from Mexico, Peru and Panama who suffered from early-stage prostate cancer were treated with the Tookad system. Two years after treatment, over 80% of the study’s subjects remained cancer-free.
A similar study being undertaken in Europe showed similar results, Steba Biotech said, and the company had submitted a marketing authorization application to the European Medicine Agency for authorization of Tookad as a treatment of localized prostate cancer.
The approved therapy was developed by Salomon and Scherz using a clever twist on photosynthesis called photodynamic therapy, in which elements are activated when they are exposed to a specific wavelength of light.
Tookad was first synthesized in Scherz’s lab from bacteriochlorophyll, the photosynthetic pigment of a type of aquatic bacteria that draw their energy supply from sunlight. Photosynthesis style, the infrared light activates Tookad (via thin optic fibers that are inserted into the cancerous prostatic tissue) which consists of oxygen and nitric oxide radicals that initiate occlusion and destruction of the tumor blood vessels.
These elements are toxic to the cancer cells and once the Tookad formula is activated, they invade the cancer cells, preventing them from absorbing oxygen and choking them until they are dead. The Tookad solution, having done its job, is supposed to then be ejected from the body, with no lingering consequences – and no more cancer.
With the drug approved for prostate cancer – and able to reach cancerous cells that are deep within the body via a minimally invasive procedure – Steba believes it may be able to treat other forms of cancer. In fact, the company said, it is also pursuing early stage studies of Tookad in esophageal cancer, urothelial carcinoma, advanced prostate cancer, renal carcinoma, and triple negative breast cancer in collaboration with Memorial Sloan Kettering Cancer Center, the Weizmann Institute, and Oxford University.
“The use of near-infrared illumination, together with the rapid clearance of the drug from the body and the unique non-thermal mechanism of action, makes it possible to safely treat large, deeply embedded cancerous tissue using a minimally invasive procedure,” according to Steba.
The Weizmann Institute has been working with Steba researchers for some 20 years to develop Tookad, said Amir Naiberg, CEO of the Yeda Research and Development Company, the Weizmann Institute’s technology transfer arm and the licensor of the therapy. “The commitment made by the shareholders of Steba and their personal relationship and effective collaboration with Weizmann Institute scientists and Yeda have enabled this tremendous accomplishment.”
“We are excited to bring a unique and innovative solution to physicians and patients for the management of low-risk prostate cancer in Mexico and subsequently to other Latin American countries,” said Raphael Harari, chief executive officer of Steba Biotech. “This approval is recognition of the tremendous effort deployed over the years by the scientists of Steba Biotech and the Weizmann Institute to develop a therapy that can control effectively low-risk prostate cancer while preserving patients’ quality of life.”
A research team from the University of Liverpool has reached an important milestone towards creating a urine diagnostic test for prostate cancer that could mean that invasive diagnostic procedures that men currently undergo eventually become a thing of the past.
‘The use of a gas chromatography (GC)-sensor system combined with advanced statistical methods towards the diagnosis of urological malignancies’, published today in the Journal of Breath Research, describes a diagnostic test using a special tool to ‘smell’ the cancer in men’s urine.
Working in collaboration with the University of the West of England’s (UWE Bristol) Urological Institute team at Southmead Hospital and Bristol Royal Infirmary, the pilot study included 155 men presenting to urology clinics. Of this group, 58 were diagnosed with prostate cancer, 24 with bladder cancer and 73 with haematuria or poor stream without cancer. The results of the pilot study using the GC sensor system indicate that it is able to successfully identify different patterns of volatile compounds that allow classification of urine samples from patients with urological cancers.
Urgent need for earlier diagnosis
Professor Chris Probert from the University of Liverpool’s Institute of Translational Medicine began work on this project with UWE Bristol when he was working in Bristol as a gastroenterologist with clinical and research interest in inflammatory bowel disease.
The research team used a gas chromatography sensor system called Odoreader that was developed by a team led by Professor Probert and Professor Norman Ratcliffe at UWE Bristol. The test involves inserting urine samples into the Odoreader that are then measured using algorithms developed by the research team at the University of Liverpool and UWE Bristol.
Professor Probert said: “There is an urgent need to identify these cancers at an earlier stage when they are more treatable as the earlier a person is diagnosed the better. After further sample testing the next step is to take this technology and put it into a user friendly format. With help from industry partners we will be able to further develop the Odoreader, which will enable it to be used where it is needed most; at a patient’s bedside, in a doctor’s surgery, in a clinic or Walk In Centre, providing fast, inexpensive, accurate results.”
Like an electronic nose
Professor Norman Ratcliffe said, “There is currently no accurate test for prostate cancer, the vagaries of the PSA test indicators can sometimes result in unnecessary biopsies, resulting in psychological toll, risk of infection from the procedure and even sometimes missing cancer cases. Our aim is to create a test that avoids this procedure at initial diagnosis by detecting cancer in a non-invasive way by smelling the disease in men’s urine. A few years ago we did similar work to detect bladder cancer following a discovery that dogs could sniff out cancer. We have been using the Odoreader, which is like an electronic nose to sense the cancer.”
“The Odoreader has a 30 metre column that enables the compounds in the urine to travel through at different rates thus breaking the sample into a readable format. This is then translated into an algorithm enabling detection of cancer by reading the patterns presented. The positioning of the prostate gland which is very close to the bladder gives the urine profile a different algorithm if the man has cancer.”
Mr Raj Prasad, Consultant Urologist at Southmead Hospital, North Bristol NHS Trust, said: “If this test succeeds at full medical trial it will revolutionise diagnostics. Even with detailed template biopsies there is a risk that we may fail to detect prostate cancer in some cases. Currently indicators such as diagnosed prostatomegaly (enlarged prostate) and unusually high PSA levels can lead to recommendations for biopsy if there is a concern that cancer may be prevalent. An accurate urine test would mean that many men who currently undergo prostate biopsy may not need to do so.”
A link to the research article in the Journal of Breath Research is given below:
Prostate cancer is one of the most common cancers. Serum prostate-specific antigen (PSA) is used to aid the selection of men undergoing biopsies. Its use remains controversial. We propose a GC-sensor algorithm system for classifying urine samples from patients with urological symptoms. This pilot study includes 155 men presenting to urology clinics, 58 were diagnosed with prostate cancer, 24 with bladder cancer and 73 with haematuria and or poor stream, without cancer. Principal component analysis (PCA) was applied to assess the discrimination achieved, while linear discriminant analysis (LDA) and support vector machine (SVM) were used as statistical models for sample classification. Leave-one-out cross-validation (LOOCV), repeated 10-fold cross-validation (10FoldCV), repeated double cross-validation (DoubleCV) and Monte Carlo permutations were applied to assess performance.
Significant separation was found between prostate cancer and control samples, bladder cancer and controls and between bladder and prostate cancer samples. For prostate cancer diagnosis, the GC/SVM system classified samples with 95% sensitivity and 96% specificity after LOOCV. For bladder cancer diagnosis, the SVM reported 96% sensitivity and 100% specificity after LOOCV, while the DoubleCV reported 87% sensitivity and 99% specificity, with SVM showing 78% and 98% sensitivity between prostate and bladder cancer samples. Evaluation of the results of the Monte Carlo permutation of class labels obtained chance-like accuracy values around 50% suggesting the observed results for bladder cancer and prostate cancer detection are not due to over fitting.
The results of the pilot study presented here indicate that the GC system is able to successfully identify patterns that allow classification of urine samples from patients with urological cancers. An accurate diagnosis based on urine samples would reduce the number of negative prostate biopsies performed, and the frequency of surveillance cystoscopy for bladder cancer patients. Larger cohort studies are planned to investigate the potential of this system. Future work may lead to non-invasive breath analyses for diagnosing urological conditions.
Other articles in this Open Access Journal related to Cancer Detection Systems include:
Pancreatic Cancer: a discovery in Toulouse that would slow its progression
Reporter: Danut Dragoi, PhD
This week was held in Toulouse edition 2016 Toulouse Onco Week (TOW), which is also supposed to end this Friday after three days of attendance. This is an event “under the patronage” of the President of the Republic, François Hollande. The event is within the framework of the World Day of fight against cancer which was held on February 4, 2016.
At TOW global oncology conference the team of the National Institute of Health and Medical Research (INSERM) in Toulouse announced their discovery, described as promising. It is about a significant advancement in the treatment against pancreaticcancer. The picture below shows a cancer cell in 3D taken from Photos: jovan vitanovski / shutterstock.com. It suggests how cancer cells attach to human organ cells. It is interesting that similar pictures were obtained with an SEM microscope.
Elimination of the CDA would stop the progress of pancreatic cancer
Working with cytidine deaminase (CDA), an enzyme familiar in the field of oncology, the scientists expected a higher sensitivity to chemotherapy, but they found another action of a modified protein, the stoppage of the progression of the tumor.
Treatment to wait in 5 to 10 years
It is stated that this advanced cancer upset was possible even before chemotherapy has not been established. The scientist Pierre Cordelier believes, however, that it will take between 5 to 10 years before this discovery will lead to a treatment. Recall that pancreatic cancer is a disease whose chances of survival appear relatively low. Indeed there are 12,000 deaths related to this tumor on the 13,000 cases reported each year. Experts expect also that pancreatic cancer from fourth to second place in the classification of causes of death by cancer.
During the TOW, the first international symposium of Toulouse Center for Cancerology Research two Nobel laureates. Professor Jules Hoffmann, winner of the 2011 Nobel Prize in Medicine, and Professor Gerd Binnig, winner of the 1986 Nobel Prize in Physics, were announced to honor the symposium with their presence.
Comment
It is interesting that the last symposium on pancreatic cancer was held in France too, at Marseilles, 2015. At that meeting there were four sessions on pancreas cancer and the high frequency of such meetings shows a sense of urgency on pancreatic cancer that is raising. In the world, India and Africa has the less rate of pancreas cancers per 100.000 people. The future of pancreas cancer is discussed in here. Pancreatic cancer is rare (it represents 2.1% of all tumors), but its incidence has increased since the middle of the 20th century. Furthermore, over 80% of patients experience a recurrence following surgery (60% of them within 6 months). In Spain, almost 4,000 new cases are recorded every year — 53% in men and 44% in women — most of whom are diagnosed between the ages of 65 and 75. In the US, the two curves, new cases and non-survivals are almost the same, the separation is only a small margin, making everybody aware of this disease.
The ubiquitin system produces a protein that greatly restricts the development of cancerous tumors.
A new study by researchers at the Technion-Israel Institute of Technology could hold one key to control cancer cell growth and development. In a paper published in the April 9, 2015 edition of CELL, the team reports on the discovery of two cancer-suppressing proteins.
Distinguished Professor Aaron Ciechanover. Photographer: Dan Porges
The research was conducted in the laboratory of Distinguished Professor Aaron Ciechanover, of the Technion Rappaport Faculty of Medicine. The team was led by research associate Dr. Yelena Kravtsova-Ivantsiv and , included additional research students and colleagues, as well as physicians from the Rambam, Carmel and Hadassah Medical Centers, who are studying tumors and their treatment.
The heretofore-undiscovered proteins were found during ongoing research on the ubiquitin system, an important and vital pathway in the life of the cell, which is responsible for the degradation of defective proteins that could damage the cell if not removed. The ubiquitin system tags these proteins and sends them for destruction in the cellular complex known as the proteasome. The system also removes functional and healthy proteins that are not needed anymore, thereby regulating the processes that these proteins control.
Usually, the proteins that reach the proteasome are completely broken down, but there are some exceptions, and the current line of research examined p105, a long precursor of a key regulator in the cell called NF-κB. It turns out that p105 can be broken down completely in certain cases following its tagging by ubiquitin, but in other cases it is only cut and shortened and becomes a protein called p50.
NF-κB has been identified as a link between inflammation and cancer. The hypothesis of the connection between inflammatory processes and cancer was first suggested in 1863 by German pathologist Rudolph Virchow, and has been confirmed over the years in a long series of studies. Ever since the discovery (nearly 30 years ago) of NF-κB, numerous articles have been published linking it to malignant transformation. It is involved in tumors of various organs (prostate, breast, lung, head and neck, large intestine, brain, etc.) in several parallel ways, including: inhibition of apoptosis (programmed cell death) normally eliminates transformed cells; acceleration of uncontrolled division of cancer cells; formation of new blood vessels (angiogenesis), which are vital to tumor growth; and increased resistance of cancerous cells to irradiation and chemotherapy.
The dramatic effect of these proteins on cancer growth: above the two tumors in the foreground (the control group) are tumors that express high levels of the proteins
As noted, the precursor p105 is “handled” by the ubiquitin system in one of two parallel and equally prevalent ways. It is either destroyed completely, or shortened and transformed to p50. The current research deciphers the decision-making mechanism that determines which process will be applied to the protein: when a ubiquitin system component called KPC1 is involved in the process and attaches ubiquitin to p105, the protein is shortened to become p50. When ubiquitination is mediated by another component of the system (and without KPC1), p105 is degraded.
The ubiquitin molecule within all living cells
The decision between these two options has significant implications on the cell, as the presence of high levels of KPC1 (which generates p50) and p50 (the product of the process) – with the accompanying disruption of the normal ratios between the processes – suppresses the malignant growth and apparently protects the healthy tissue. The current research was conducted on models of human tumors grown in mice, as well as on samples of human tumors, and a strong connection was discovered between the suppression of malignancy and the level of the two proteins, clearly indicating that the increased presence of KPC1 and/or p50 in the tissue can protect it from cancerous tumors.
Professor Ciechanover, who is also the president of the Israel Cancer Society, notes that many more years are required “to establish the research and gain a solid understanding of the mechanisms behind the suppression of the tumors. The development of a drug based on this discovery is a possibility, although not a certainty, and the road to such a drug is long and far from simple.”
Professor Ciechanover won the Nobel Prize in Chemistry in 2004 (jointly with Professors Avram Hershko – also from the Technion – and Irwin Rose, of the Fox Chase Cancer Center) for the discovery of the ubiquitin system. The current line of research is a continuation of that discovery.
President Reuven Rivlin and Indian Prime Minister Narendra Modi, March 29, 2015 (photo credit: Courtesty Tomer Reichmann)
President Reuven Rivlin and Indian Prime Minister Narendra Modi, March 29, 2015 (photo credit: Courtesty Tomer Reichmann)
Days after the Technion announced that a team led by Nobel Prize laureate Professor Aaron Ciechanover had discovered how proteins could be used to suppress cancer and control tumor growth and development, the institute revealed that it had entered into an exclusive agreement with India’s Sun Pharmaceuticals — the world’s fifth-largest specialty generic pharmaceutical company and India’s top pharmaceutical company.
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Under the agreement, researchers from the Technion and Sun will conduct studies on how high concentrations of two proteins can protect tissue from tumors. A study published in the medical journal Cell this week discussed how the proteins can suppress malignancies.
Along with Ciechanover, the research team included Dr. Gila Maor and Professor Ofer Binah. In a statement, Ciechanover said that the research held a great deal of promise of an effective drug for treating cancer, “although this is not a certainty, and the road to such a drug is long and far from simple.”
The deal with Sun is just one of several R&D ventures between Israel and India, on both the business and government levels. So far, the two countries have signed seven bilateral economic and R&D agreements, including one that fosters joint projects on space travel and satellite development.
The joint program aims at attracting additional, world-class support from institutions and individuals who are dedicated to eradicating cancer through focused and efficient research.
Two of the world’s preeminent academic and research institutions — New York University’s Langone Medical Center and Haifa’sTechnion-Israel Institute of Technology — have made a “groundbreaking step forward to advance global collaboration in the fight against cancer formally.
On Wednesday night, they announced a $9 million gift from philanthropists Laura and Isaac Perlmutter that will fund two major, joint research endeavors with potentially far-reaching impact in advancing cancer research. The joint program aims at attracting additional, world-class support from institutions and individuals who are dedicated to eradicating cancer through focused and efficient research, they said in a joint statement.
The first $3 million of the grant will finance six cancer-focused research projects to be conducted by teams spearheaded by co-investigators from both NYU and the Technion. The remaining $6 million will be used to establish a state-of-the-art research facility on Technion’s campus that will support these and other research projects and focus mainly on the emerging field of cancer metabolomics.
“NYU Langone and the Technion have a shared, longstanding commitment to advancing cancer research,” said Dr. Dafna Bar-Sagi, senior vice president and vice dean for science at the New York hospital, chief science officer at NYU School of Medicine and a principal architect of the NYU Langone-Technion partnership. “We are now at a great moment in our institutions’ illustrious histories, a point from which we can jointly leverage the talent and creativity of our researchers toward accelerating breakthroughs. The foresight and the generosity of the Perlmutters, particularly at this time of financial challenge in funding for basic research, will have tremendous impact.”
“Bringing together the unique expertise of researchers from both NYU and the Technion will hopefully enable us to overcome some of the most difficult challenges in treating cancer patients,” said Technion Prof. Aaron Ciechanover, the 2004 Nobel Prize Laureate in Chemistry and Distinguished Research Professor and head of the David and Janet Polak Cancer and Vascular Biology Research Center at the Technion Faculty of Medicine.
Renowned cancer biologist Dr. Benjamin Neel, an expert in the field of cell signal transduction, recently joined the Langone faculty as director of the Perlmutter Cancer Center, and Dr. Eyal Gottlieb, a world leader in cancer metabolism, has been recruited to lead the new research facility at the Technion funded by the Perlmutter gift. Neel will work closely with Ciechanover to lead the collaborative cancer research effort between the two institutions, they said.
In addition, Neel will oversee at NYU the building of world-class translational programs in immunotherapy, cancer genetics/targeted therapies and epigenetics, imaging, as well as expanded programs in clinical care, community outreach and supportive oncology.
The innovative method, developed at the Technion, identifies persons at risk for developing stomach cancer and for detecting tumors at an earlier stage. The prestigious journal Gut, which published the research, notes that the detection method is quick, simple, inexpensive and non-invasive.
Innovative gastric cancer-detection technology
Innovative gastric cancer-detection technology developed by the Technion can be used for the early detection of stomach cancer and for identifying persons at risk for developing the disease. The new detection method, based on breath analysis, has significant advantages over the existing detection technology: Gut reports that the new method is quick, simple, inexpensive and non-invasive.
Gastric cancer is one of the most lethal forms of cancer and in most cases, its diagnosis involves an endoscopy (the insertion of a tube into the esophagus, requiring that the patient fast and receive an intravenous sedative). Treatment is aggressive chemotherapy, radiation and the full or partial removal of the stomach. The disease develops in a series of well-defined steps, but there’s currently no effective, reliable, and non-invasive screening test for picking up these changes early on. Thus, many people succumb to stomach cancer only because it was not diagnosed in time.
The new technology, developed by Prof. Hossam Haick of the Wolfson Faculty of Chemical Engineering, can be used to detect premalignant lesions at the earliest stage, when healthy cells start becoming cancerous.
The research, published in Gut as part of the doctoral thesis of Mr. Haitham Amal, was conducted in conjunction with a Latvian research group headed by Prof. Marcis Leja, based on the largest population sample ever in a trial of this type. 484 people participated in the trial, 99 of whom had already been diagnosed with stomach cancer. All the participants were tested for Helicobacter pylori, a bacterium known to increase the risk for stomach cancer, and two breath samples were taken from each person.
The first sample from each participant was analyzed using the GCMS technique, which measures volatile organic substances in exhaled breath. The researchers noted that GCMS technology cannot be used to detect stomach cancer because the testing is very expensive and requires lengthy processing times and considerable expertise to operate the equipment.
The second breath sample was tested using nanoarray analysis, the unique technology developed by Prof. Haick, combined with a pattern recognition algorithm.
The findings:
Based on the concentrations of 8 specific substances (out of 130) in the oral cavity, the new technology can distinguish between three groups: gastric cancer patients, persons who have precancerous stomach lesions, and healthy individuals.
The new technology accurately distinguishes between the various pre-malignant stages.
The new technology can be used to identify persons at risk for developing gastric cancer.
The diagnosis is accurate, regardless of other factors such as age, sex, smoking habits, alcohol consumption and the use of anti-oxidant drugs.
In short, the nano-array analysis method developed by Prof. Haick is accurate, sensitive technology that provides a simple and inexpensive alternative to existing tests (such as GCMS). This new technology offers early, effective detection of persons at risk for developing stomach cancer, without unnecessary invasive tests (endoscopy). In order to assess the accuracy and effectiveness of the new, a wide-scale clinical trial is currently under way in Europe, with thousands of participants who have cancerous or pre-cancerous tumors.
About Prof. Hossam Haick
Prof. Hossam Haick, who joined the senior staff at the Technion Wolfson Faculty of Chemical Engineering in 2006, has been working since that year on the development of innovative, non-invasive technology for detecting cancer and other diseases. This technology is based on an “electronic nose” – an apparatus capable of detecting illnesses by analyzing a patient’s exhaled breath.
Prof. Haick, a native of Nazareth, completed his Ph.D. studies at the Technion by the time he was 27 and went to the Weizmann Institute of Science in Rehovot and Caltech Institute of Technology in California. He returned to the Technion in 2006 and his research group was awarded one million euros in grants by the European Union, which was very impressed by his research into artificial olfactory systems. Today he heads a consortium that includes Siemens and several universities, research institutes and companies in Germany, Austria, Finland, Ireland, Latvia and Israel. Since joining the senior faculty in the Chemical Engineering Department in 2006, Prof. Haick has won dozens of awards, grants and international honors. These include the Marie Curie Excellence Grant, European Research Council (ERC) grant and the Bill & Melinda Gates Award. Prof. Haick was nominated to MIT’s list of the 35 leading young scientists worldwide, received the Knight of the Order of Academic Palms, from the French Government and won the Hershel Rich Technion Innovation Award (twice), as well as the Tenne Prize for Excellence in the Science of Nanotechnology. He has also been recognized for his outstanding teaching skills and is the recipient of the Yanai Prize for Academic Excellence. In 2014, at the initiative of the president of the Technion, Prof. Haick headed an MOOC (Massive Open Online Course) in nanotechnology and nano-sensors that had an enrollment of 42,000.
This month is Breast Cancer Awareness Month in Israel and around the world. Innovative technology developed at the Technion Faculty of Biomedical Engineering will enable the prediction of cancer metastasis after the appearance of breast cancer. The technology, whose efficacy has been proven in preliminary laboratory-trials, is entering into advanced testing using cells from patients undergoing surgery.
In contrast to benign cells (right), metastatic cells (left) penetrate into the gel and disappear inside it, thanks to their unique characteristics
Assistant Professor Daphne Weihs recently achieved a research breakthrough: the unique technology that she developed – a biomechanical method for early detection of metastatic cancer – was approved by the Ethics Committee. This means that the technology that was found to be effective in tests on cell lines will advance to trials with tumor cells collected directly after surgery, in cooperation with Rambam Healthcare Campus.
According to Assistant Professor Weihs, the practical concept is that “during or immediately after a biopsy or surgery on a malignant tumor, the system will enable the medical team to quantitatively evaluate the likelihood of the presence or development of tumor metastases in other organs, and to propose which organ or organs are involved. Such knowledge will make it possible to act at a very early stage to identify and curb these metastases and, moreover, to prevent the primary tumor from metastasizing further.
Cancer is a general name for a wide family of diseases – more than 200 – whose common denominator is that the cell division rate becomes uncontrolled and the cells become immortal. In other words, the cancer mechanism disrupts the normal cell division process and converts it into “wild” and rapid division. Since the cells do not age and do not die, the original, primary tumor expands, invades and takes over more and more nearby tissue. In addition, apart from spreading to its immediate vicinity, a tumor that has become very aggressive “knows” how to send metastases to more distant tissues through the lymph and circulatory systems. Metastases (secondary tumors) are usually more dangerous than the primary tumor because it is difficult to identify them at their inception. When they are detected at an advanced stage, treating them medically is more complicated and the medical prognosis is typically not good.
“In fact, most cancer-related deaths are caused by metastases rather than by the primary tumor, and therefore vast resources are invested in developing methods for early detection of metastases,” explains Assistant Professor Daphne Weihs. “Early detection means timely and more effective treatment. The new approach that we are developing will enable early prediction of the likelihood of the formation of metastases and where in the body their development is probable. This prediction is based on identifying the biomechanics of the primary tumor cells, and does not require us to know the specific genetic makeup of the tumor.”
Diagnostic system developed by Technion professor is to pair with tiny smell-sensitive sensor that can go anywhere
By David Shamah February 3, 2015, 2:05 pm
A patient uses the NaNose breathalyzer (Photo credit: Courtesy Technion)
Writers
David Shamah
An innovative early disease detection system that uses the sense of smell is going mobile.
The NaNose breathalyzer technology developed by Professor Hossam Haick of the Technion will soon be installed in a mobile phone – to be called, appropriately, the SniffPhone. A tiny smell-sensitive sensor will be installed onto a phone add-on, and using specially designed software, the phone will be able to “smell” users’ breath to determine if they have cancer, among other serious diseases.
By identifying the special “odor” emitted by cancer cells, the NaNose system can detect the presence of tumors, both benign and malignant, more quickly, efficiently and cheaply than previously possible, said Haick.
“Current cancer diagnosis techniques are ineffective and impractical,” he said. NaNose technology, he said, “could facilitate faster therapeutic intervention, replacing expensive and time-consuming clinical follow-up that would eventually lead to the same intervention.”
According to research done by Haick’s team, the NaNose system has a 90 percent accuracy rate.
The smartphone device is just a vehicle to implement the NaNose technology that can be taken anywhere and used in any circumstances, including in rural areas of the developing world where bringing in sophisticated testing equipment is impossible.
The plan calls for a chip with NaNose technology to be installed in a device that is attached to a smartphone, and for an app to read the sensor data, analyzing it on the device or uploading it to the cloud for processing.
NaNose technology will be especially useful in battling lung cancer, said Haick. According to US government statistics, lung cancer kills more Americans annually than the next three most common cancers — colon, breast, and pancreatic — combined. The reason, doctors say, is because lung cancer is so difficult to detect. Currently, the only way to detect early-stage lung cancer is through an extensive process involving blood tests, biopsies, CT scans, ultrasound tests, and other procedures — and even then, detection is difficult.
“Mostly the patient arrives for diagnosis when the symptoms of the sickness have already begun to appear,” said Haick, describing the drawbacks in current detection protocols. “Months pass before a real analysis in completed. And the process requires complicated and expensive equipment such as CT and mammography imaging devices. Each machine costs millions of dollars, and ends up delivering rough, inaccurate results.”
Dr. Hossam Haick (Photo credit: Courtesy)
The NaNose-based system, on the other hand, doesn’t require anything more than a patient’s breathing into the device in order to come up with an initial diagnosis. Lung cancer tumors produce chemicals called volatile organic compounds (VOCs), which easily evaporate into the air and produce a discernible scent profile. Haick’s NaNose chip detects the unique “signature” of VOCs in exhaled breath. In four out of five cases, the device differentiated between benign and malignant lung lesions and even different cancer subtypes.
The project is being funded by the European Commission, which has given the consortium developing it a six million euro grant. The developers include universities and research institutes from Germany, Austria, Finland, Ireland and Latvia, as well as Irish cell biology research firm Cellix, with the NaNose system the centerpiece of the technology. That Israeli-developed component will be delivered by an Israeli start-up called NanoVation-GS, a spinoff of the Technion. Professor Haick serves as the start-up’s Chief Science Officer.
“The SniffPhone is a winning solution. It will be made tinier and cheaper than disease detection solutions currently, consume little power, and most importantly, it will enable immediate and early diagnosis that is both accurate and non-invasive,” said Haick. “Early diagnosis can save lives, particularly in life-threatening diseases such as cancer.”
Anyone who knows a person in the midst of chemotherapy is aware that anti-cancer drugs often take a very harsh toll on the body. This is one reason scientists have been trying to develop improved means of drug delivery for years. Now, a Technion research team discovered a way to improve drug delivery to tumors using Nanostructured Porous Silicon (PSi) particles (instead of an IV drip), a method that’s emerging as a promising new platform for drug delivery. In the future, PSi could be used in cancer treatments, potentially offering an alternative to traditional chemotherapy, which is notorious for its agonizing side effects.
The silicon “carriers” used in this study to deliver chemotherapy drugs behave differently in cancerous tumors than they do in healthy tissues. Therefore, the findings could help scientists to design nano-carriers that deliver drugs to tumors, instead of treating patients with traditional, intravenous chemotherapy. However, it would take years to develop and apply this new type of drug delivery method, which would potentially be taken orally.
So far, these nano-silicon “containers” have been studied in vitro – outside of a living organism – rather than in an environment that behaves more closely to that of a tumor in a cancer patient’s body. The Technion research team looked at what happens to PSi particles when they’re injected into the area around the tumor in mice. The significant differences in the area around a cancerous growth and regular healthy tissue have been widely described and studied; however, the effect on these porous silicon “containers,” or carriers, was unknown until now.
Prof. Ester Segal of the Technion – Israel Institute of Technology, who led this joint study with the Massachusetts Institute of Technology (MIT) and the Harvard Medical School, said the team has “shown for the first time that bio-materials in general, and Nanostructured Porous Silicon in particular, behave differently when they are injected (or implanted) at the tumor micro-environment.”
Revolutionizing cancer treatments
Silicon materials could revolutionize treatments in a way that no existing drug delivery does. Prof. Segal tells NoCamels that the silicon containers “could deliver drugs over a long period of time – weeks or even months”, something no existing chemotherapeutic delivery mechanism can do currently.
Cancer cells
The special properties of these porous nano-silicon carriers lie in their large surface area, which can ferry many or large drug molecules. Additionally, due to their biodegradability they’re able to break down into harmless silicic acid, which is expelled through urination. They are also biocompatible, so they do not stimulate any inflammation or clotting. Another benefit to these nano-silicon containers is their versatility. They can be ingested, injected or implanted, and they can be designed to carry a wide range of dosage sizes. In the process of their study, lab members also developed an approach to determining how biomaterials will react in settings more similar to their eventual clinical purpose – treating cancer, for example.
In a separate study, Tel Aviv University scientists recently founda strategy that would stop brain tumor cell proliferation with similar nano-particles. “It is a basic, elegant mechanism and much less toxic than chemotherapy,” TAU’s Prof. Dan Peer said in a statement.
These works underline the importance of such studies in successfully developing bio-delivery materials that will have therapeutic benefits in the near future.
“Nano-skeletons’ (in red) delivered to human tissue infected by prostate cancer. The infected cells are colored in blue (PIP) and green (cytoplasmic); it is possible to see how the ‘nano-skeletons’ reach them
Florida native Dr. Beth Schoen, is part of a team developing a novel platform for delivering anti-cancerous drugs directly to its mark as part of her postdoctoral research at the Technion
Beth Schoen, born in Hollywood Florida, came to the Technion to conduct her postdoctoral research at age 26. In her very limited spare time she plays soccer for the leading all women’s soccer team – Maccabi Hadera – and studies Hebrew. “The Hebrew thing is no simple matter,” she confesses, “but I’m willing to make the effort, because it’s clear to me that Israel is where I want to live.”
Dr. Beth Schoen completed her undergraduate degree at the University of Florida, and her doctorate at Michigan State University in chemical engineering. “My doctoral studies focused on synthetic organic chemistry, particularly on the development of polymers with unique thermodynamic attributes especially resistant to high temperatures. These types of materials are used in part for the production of jet engine parts, body armor and Nomex (used for making fire-resistant gloves and overalls). One of our tasks was to create soft sheets that were not brittle, to be worn to be both bulletproof and fire resistant. It was a theoretical study, but as part of the process I also produced some of these polymers and tested them.”
Dr. Schoen planned to come to the Technion as part of her doctoral studies, but, she adds, “It didn’t work out, so I started to check where I could best fit in here in my future studies.” She decided to join Prof. Marcelle Machluf’s laboratory, at the Faculty of Biotechnology and Food Engineering, “I was eager to move from chemistry to biology and pursue cancer research in particular. I was very glad for the tremendous opportunity that Marcelle gave me in taking me on – perhaps it was because of my experience in nanomaterials and polymers.”
Prof. Marcelle Machluf’s research team consists of 17 female and 3 males students, researchers and technicians working on two main projects: (1) the development of scaffolds to rehabilitate damaged heart-tissue, and (2) the development of new technology to deliver drug treatment to damaged (sick) tissue (specifically related to cancer therapy). In an interview with her she focused on the second project.
“The current treatment for cancer involves radiotherapy and chemotherapy usually administered through intravenous infusion. The cancer drugs available are extremely effective, yet the way they are put to use in present day treatment, they also cause damage to healthy tissues. These are very potent drugs – they are intended to kill cancer cells – and on their way they also end up killing healthy ones.”
“The greatest damage is caused to rapidly dividing cells, which are similar to cancer cells. Hair follicle cells, for example, are a type of rapidly dividing cells and they damage easily from these types of treatment, which explains the hair loss in patients undergoing chemotherapy. Other side-effects include nausea and hearing loss, sometimes even leading to deafness. The drug Cisplatin for example, is a type of chemo drug used to treat various types of lung and breast cancers; some of its side-effects include damage to renal and immune system functioning, putting patients at risk to infections and diseases.”
These impediments are what fuel Prof. Machluf’s drive to develop a new drug delivery platforms capable of delivering anti-cancer drugs directly to the tumor without damaging healthy tissues on its way. “This is the top priority of cancer treatment: to develop a ‘magic bullet’ that target cancer cells,” explains Prof. Machluf. “And our new platform may be the solution to this great challenge.”
The new platform is based on ‘depleting’ specific cells – mesenchymal stem cells – so that there is nothing left of them save for the membrane. This membrane, called a ghost cells can be down sized to nano-vesicles, termed nano-ghosts, which can be loaded with any drug and delivered by injection directly into the blood stream. The immune system falls for the trap and does not recognize the ‘intruder,’ instead it treats these cells as if they were naturally part of the system and sends them to the afflicted area. On the way to their target they do not release the drug they are carrying and therefore do not do any damage to healthy tissues. Only upon reaching the malignant tissue, which they know how to identify, do they break down and secrete their contents at the site of the tumor cells.
This original idea was tested in a long series of experiments, and the results are very impressive: these nano-ghosts are in fact tumor selective, no matter the type of tumor. They ‘dash’ straight to the malignant tissue without emitting their drug on the way and without damaging healthy cells. Moreover, this unique ‘parcel’ increases the effectiveness of the treatment by ten-fold. Animal studies have shown that the employment of nano-ghosts for anti-cancer drug delivery have led to an 80% delay of prostate cancer – an unprecedented rate.
Still, there is a lot of work ahead, as Prof. Machluf’s research team works on improving the mechanism of this novel new platform: some of them are focusing on compatibility with specific drugs while others, like Dr. Beth Schoen, are concentrating on improving the nano-ghosts “This platform must be very precise,” explains Schoen. “It must be able to endure travelling through the entire human body, and release its contents only inside the tumor.”
Live Notes from @AACR’s #cbi16 Meeting on Precision Medicine: 3:45PM Big Idea Dr. Hait and Premalignancy
Big Idea: Interception: Search for therapies that can tackle pre-malignancies to prevent cancer by Dr. Williams Hait, Global Head Drug Discovery Jansenn
Reporter: Stephen J. Williams, Ph.D.
We accumulate diseases over our lifetime
Jannsen decided to come up with the term “immorbidity” living longer without fear of disease
genetic complexity of cancers increase over time Nature 2012 paper
with Gleevec different relapse picture with early than advanced disease (see my post on Gleevec resistance)
cancer prevention screens have been important (Pap smears, colonoscopies)
MGuS (myeloma precursor) to SMM then full blown disease
huge knowledge gap in premalignant myeloma disease and karyotypic changes
Live Notes From AACR TownHall on Precision Medicine January 21, 2016 in Philadelphia, PA: Background Information on Speakers
Reporter: Stephen J. Williams, Ph.D.
The Speakers:
Chief Executive Officer Margaret Foti, PhD, MD (hc)
American Association for Cancer Research
Philadelphia, Pennsylvania
Margaret Foti, PhD, MD (hc), is the chief executive officer of the American Association for Cancer Research (AACR), the oldest cancer research organization in the world. Under her visionary leadership, membership has grown from about 3,000 members to 35,000 in 101 countries and the AACR’s portfolio of peer-reviewed scientific journals has increased from one to eight.
Chi Van Dang, MD, PhD
John H. Glick, M.D. Abramson Cancer Center Director’s Professor
Director, Abramson Cancer Center, University of Pennsylvania
Selected Publications:
Koppenol WH, Bounds PL, Dang CV: Otto Warburg’s contributions to current concepts of cancer metabolism. Nature Reviews Cancer 11 (5): 325-337,2011.
Dang CV, Hamaker M, Sun P, Le A, Gao P: Therapeutic targeting of cancer cell metabolism Journal of Molecular Medicine 89 (3): 205-212,2011.
Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG, Ferraris DV, Tsukamoto T, Rojas C, Slusher BS, Rabinowitz JD, Dang CV, Riggins GJ: Inhibition of Glutaminase Preferentially Slows Growth of Glioma Cells with Mutant IDH1. Cancer Research 70 (22): 8981-8987,2010.
Otto AE, Hurd TW, Airik R, Chaki M, Zhou W, Stoetzel C, Patil SB, Levy S, Ghosh A K, Murga-Zamalloa CA, van Reeuwijk J, Letteboer SJF, Sang L, Giles RH, Liu Q, Coene KLM, Estrada-CuzcanA, Collin RWJ, McLaughlin HM, Held S, Kasanuki JM, Ramaswami G, Conte J, Lopez I, Washburn J, MacDonald J, Hu J, Yamashita Y, Maher ER, Guay-Woodford L, Neumann HPH, Obermüller N, Koenekoop RK, Bergmann C, Bei X, Lewis RA, Katsanis N, Lopes V, Williams DS, Lyons RH, Dang CV, Brito DA, Zhang X, Dias MB, Nürnberg G, Nürnberg P: Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nature Genetics 42 (10): 840-50,2010.
Dang CV: Glutaminolysis Supplying carbon or nitrogen or both for cancer cells? Cell Cycle 9 (19): 3884-3886,2010.
Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, Wilson KF, Ambrosio ALB, Dias SMG, Dang CV, Cerione RA: Targeting Mitochondrial Glutaminase Activity Inhibits Oncogenic Transformation. Cancer Cell 18 (3): 207-219,2010.
Koh, CM, Bierberich CJ, Dang CV, Nelson WG, Yegnaubramanian S, De Marzo A: Myc and prostate cancer. Genes & Cancer 1 (6): 617-628,2010.
Fan J, Zeller K, Chen YC, Watkins T, Barnes KC, Becker KG, Dang CV, Cheadle C: Time-Dependent c-Myc Transactomes Mapped by Array-Based Nuclear Run-On Reveal Transcriptional Modules in Human B Cells. Plos One 5 (3): e9691,2010.
Dang CV: p32 (C1QBP) and Cancer Cell Metabolism: Is the Warburg Effect a Lot of Hot Air? Molecular And Cellular Biology 30 (6): 1300-1302,2010.
Stephan A. Grupp, MD, PhD, is director of the Cancer Immunotherapy Frontier Program, director of Translational Research for the Center for Childhood Cancer Research at CHOP and medical director of the Stem Cell Laboratory.
Areas of Expertise: Development of engineered T cell therapies such as CTL019, Novel leukemia therapy, Stem cell transplants, Treatment of high-risk neuroblastoma
Working with our colleagues at the University of Pennsylvania, we have recently opened a phase I clinical trial called CART19. We’re using genetically modified T cells in this trial to treat patients with B cell cancers such as ALL, B cell non-Hodgkin lymphoma (NHL), the adult disease chronic lymphocytic leukemia and other B cell malignancies. T cells have the potential to kill cancer cells, but in patients with cancer, they’re not doing their job. By modifying them we can make the cells behave differently so they’ll attack cancer cells, using an engineered targeting protein called a chimeric antigen receptor (CAR). Initial results show that this could be an effective therapy for patients with B cell cancers. Indeed, our initial results show some of the most powerful activity against cancer of any clinical trial testing engineered cell therapy to date. This has received international attention, and some of this work has been published recently in Science Translational Medicine and the New England Journal of Medicine.
Prostate cancer is the most commonly diagnosed malignancy in the Unites States and the second leading cause of cancer death in men. Early prostate cancers require androgen to survive and proliferate; this dependence is exploited in treatment for disseminated disease. Wherein androgen ablation in the first line of therapeutic intervention. Although these regimens are initially effective, tumors ultimately recur due to reactivation of androgen receptor (AR) signaling, causing treatment failure and patient morbidity.
Despite the importance of understanding androgen action in the prostate, little is understood about the mechanisms underlying androgen dependence, and the means by which the androgen requirement is bypassed in relapsed tumors. My lab is dedicated to delineating the molecular mechanisms that govern these events. We currently have four main projects in the lab:
1. Regulation of AR dependent gene expression and cellular proliferation by cell cycle crosstalk in prostate cancer
2. Impact of SWI/SNF chromatin remodeling factors on AR function and prostate tumorigenesis
3. Impact of cell cycle deregulation on therapeutic efficacy
4. Role of endocrine disrupting compounds in circumventing the androgen requirement
By studying disease modifier genes we seek to develop new principles to treat cancer, diabetes, autoimmune disorders and cardiovascular disease. Currently most biomedical research focuses on understanding disease pathways. We seek to understand general disease modifier pathways that determine disease severity, an understudied area from which many useful drugs such as NSAIDs and statins are based. A major thrust of our present work focuses on modifiers of inflammatory processes which contribute significantly to the severity of many age-associated diseases. In our main project, we have developed a new class of drugs that recruit the immune system to eradicate a broad spectrum of advanced cancers, including breast, lung, skin, and pancreas tumors that are often refractory to chemotherapy. These drugs, called IDO inhibitors, are presently in Phase II clinical trials. In other projects, with our Lankenau colleagues we are developing new agents to treat autoimmune disorders, reduce risks of cardiovascular disease, and ameliorate diabetes.
Scientific Description
Our laboratory is interested primarily in cancer genes, cancer immunology and molecular therapeutics. We use transgenic mouse models and preclinical drug strategies to learn new ways to suppress cancer, focusing on long-term goals of improving strategies for cancer prognosis and treatment.
Localized tumors are often curable if they are detected before progression to invasive status, but many patients diagnosed with cancer already have invasive disease. What factors dictate malignant progression and how might they be therapeutically exploited? Molecular therapeutics that target key oncogene and tumor suppressor pathways show some clinical promise, but they have shown limited efficacy to date. Cancer modifier pathways that influence the immune microenvironment of tumor cells may strongly influence clinical course. Accordingly, new therapies we are developing are based on blocking enzymes that limit the ability of immune cells to destroy cancer cells or drive disease.
RhoB studies derive from our long-standing research on this member of the Ras/Rho superfamily in cancer cell signaling. Recent work in collaboration with Drs. Lisa Laury-Kleintop and Laura Mandik-Nayak at Lankenau has opened exciting new directions in studies of the role of RhoB in autoimmune and cardiovascular disease. A start-up company has been created to fund and advance the preclinical and clinical work needed to explore a provocative new therapy emerging from these novel directions, which in principle may be useful to treat one or more diseases in important areas of medicine.
Bin1 studies originating in cancer cell studies led us to discover that it regulates the immune modulatory enzyme indoleamine 2,3-dioxygenase (IDO). Bin1 modifies inflammation in a variety of settings including cancer. Recently, in preclinical studies we found that its genetic blockade can limit the development of inflammatory bowel disease (colitis). Based on this finding, we are now investigating the use of Bin1 antibodies we have developed to treat this disorder.
IDO is a tryptophan catabolic enzyme that blocks T cell activation in physiological settings such as pregnancy and in many pathophysiological settings like cancer. IDO is very widely activated as a mechanism of immune escape by cancer cells. Genetic studies reveal that IDO is essential for inflammation-driven cancers, not only supporting immune escape but also angiogenesis and metastasis. We pioneered preclinical studies of IDO inhibitory drugs that can arrest tumor growth and enhance chemotherapeutic efficacy. Mechanistic studies of one clinical lead inhibitor, D-1MT (indoximod), will greatly assist ongoing Phase II studies of this drug. Translational studies including on an IDO-related gene called IDO2 discovered at Lankenau are currently a major focus of the laboratory.
Please Follow on Twitter @pharma_BI and @AACR using meeting #cbi16
Multiple factors related to initial trial design may predict low patient accrual for cancer clinical trials
Reporter: Stephen J. Williams, Ph.D.
UPDATED 5/15/2019
A recently published paper in JCNI highlights results determining factors which may affect cancer trial patient accrual and the development of a predictive model of accrual issues based on those factors.
Nearly one in four publicly sponsored cancer clinical trials fail to enroll enough participants to draw valid conclusions about treatments or techniques. Such trials represent a waste of scarce human and economic resources and contribute little to medical knowledge. Although many studies have investigated the perceived barriers to accrual from the patient or provider perspective, very few have taken a trial-level view and asked why certain trials are able to accrue patients faster than expected while others fail to attract even a fraction of the intended number of participants. According to a study published December 29 in the JNCI: Journal of the National Cancer Institute, a number of measurable trial characteristics are predictive of low patient accrual.
Caroline S. Bennette, M.P.H., Ph.D., of the Pharmaceutical Outcomes Research and Policy Program, University of Washington, Seattle, and colleagues from the University of Washington and the Fred Hutchinson Cancer Research Center analyzed information on 787 phase II/III clinical trials sponsored by the National Clinical Trials Network (NCTN; formerly the Cooperative Group Program) launched between 2000 and 2011. After excluding trials that closed because of toxicity or interim results, Bennette et al. found that 145 (18%) of NCTN trials closed with low accrual or were accruing at less than 50% of target accrual 3 years or more after opening.
The authors identified potential risk factors from the literature and interviews with clinical trial experts and found multiple trial-level factors that were associated with poor accrual to NCTN trials, such as increased competition for patients from currently ongoing trials, planning to enroll a higher proportion of the available patient population, and not evaluating a new investigational agent or targeted therapy. Bennette et al. then developed a multivariable prediction model of low accrual using 12 trial-level risk factors, which they reported had good agreement between predicted and observed risks of low accrual in a preliminary validation using 46 trials opened between 2012 and 2013.
The researchers conclude that “Systematically considering the overall influence of these factors could aid in the design and prioritization of future clinical trials…” and that this research provides a response to the recent directive from the Institute of Medicine to “improve selection, support, and completion of publicly funded cancer clinical trials.”
In an accompanying editorial, Derek Raghavan, M.D., Levine Cancer Institute, writes that the focus needs to be on getting more patients involved in trials, saying, “we should strive to improve trial enrollment, giving the associated potential for improved results. Whether the basis is incidental, because of case selection bias, or reflects the support available to trial patients has not been determined, but the fact remains that outcomes are better.”
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Contact info:
Article: Caroline S. Bennette, M.P.H., Ph.D., cb11@u.washington.edu
Other investigators also feel that initial trial design is of UTMOST importance for other reasons, especially in the era of “precision” or “personalized” medicine and why the “basket trial” or one size fits all trial strategy is not always feasible.
Dr. Maurie Markman, MD gives insight into why the inital setup of a trial and the multi-center basket type of accrual can be a problematic factor in obtaining meaningful cohorts of patients with the correct mutational spectrum.
The anticancer clinical research paradigm has rapidly evolved so that subject selection is increasingly based on the presence or absence of a particular molecular biomarker in the individual patient’s malignancy. Even where eligibility does not mandate the presence of specific biological features, tumor samples are commonly collected and an attempt is subsequently made to relate a particular outcome (eg, complete or partial objective response rate; progression-free or overall survival) to the individual cancer’s molecular characteristics.
One important result of this effort has been the recognition that there are an increasing number of patient subsets within what was previously—and incorrectly—considered a much larger homogenous patient population; for example, non–small cell lung cancer (NSCLC) versus EGFR-mutation–positive NSCLC. And, while it may still be possible to conduct phase III randomized trials involving a relatively limited percentage of patients within a large malignant entity, extensive and quite expensive effort may be required to complete this task. For example, the industry-sponsored phase III trial comparing first-line crizotinib with chemotherapy (pemetrexed plus either carboplatin or cisplatin) in ALK-rearrangement–positive NSCLC, which constitutes 3% to 5% of NSCLCs, required an international multicenter effort lasting 2.5 years to accrue the required number of research subjects.1
But what if an investigator, research team, or biotech company desired to examine the clinical utility of an antineoplastic in a patient population representing an even smaller proportion of patients with NSCLC such as in the 1% of the patient population with ROS1 abnormalities,2 or in a larger percentage of patients representing 4%-6% of patients with a less common tumor type such as ovarian cancer? How realistic is it that such a randomized trial could ever be conducted?
Further, considering the resources required to initiate and successfully conduct a multicenter international phase III registration study, it is more than likely that in the near future only the largest pharmaceutical companies will be in a position to definitively test the clinical utility of an antineoplastic in a given clinical situation.
One proposal to begin to explore the benefits of targeted antineoplastics in the setting of specific molecular abnormalities has been to develop a socalled “basket trial” where patients with different types of cancers with varying treatment histories may be permitted entry, assuming a well-defined molecular target is present within their cancer. Of interest, several pharmaceutical companies have initiated such clinical research efforts.
Yet although basket trials represent an important research advance, they may not provide the answer to the molecular complexities of cancer that many investigators believe they will. The research establishment will have to take another step toward innovation to “N-of-1” designs that truly explore the unique nature of each individual’s cancer.
Trial Illustrates Weaknesses
A recent report of the results of one multicenter basket trial focused on thoracic cancers demonstrates both the strengths but also a major fundamental weakness of the basket trial approach.3
However, the investigators were forced to conclude that despite accrual of more than 600 patients onto a study conducted at two centers over a period of approximately 2 years, “this basket trial design was not feasible for many of the arms with rare mutations.”3
They concluded that they needed a larger number of participating institutions and the ability to adapt the design for different drugs and mutations. So the question to be asked is as follows: Is the basket-type approach the only alternative to evaluate the clinical relevance of a targeted antineoplastic in the presence of a specific molecular abnormality?
Of course, the correct answer to this question is surely: No!
The following is a video on the website ClinicalTrials.gov which is a one-stop service called EveryClinicalTrial to easily register new clinical trials and streamline the process:
UPDATED 5/15/2019
Another possible roadblock to patient accrual has always been the fragmentation of information concerning the availability of clinical trails and coordinating access among the various trial centers, as well as performing analytics on trial data to direct new therapeutic directions. The NIH has attempted to circumvent this problem with the cancer trials webpage trials.gov however going through the vast number of trials, patient accrual requirements, and finding contact information is a daunting task. However certain clinical trial marketplaces are now being developed which may ease access problems to clinical trials as well as data analytic issues, as highlighted by the Scientist.com article below:
Scientist.com Launches Trial Insights, A Transformative Clinical Trials Data Analytics Solution
The world’s largest online marketplace rolls out first original service, empowering researchers with on demand insights into clinical trials to help drive therapeutic decisions
SAN DIEGO–(BUSINESS WIRE)–Scientist.com, the online marketplace for outsourced research, announced today the launch of Trial Insights, a digital reporting solution that simplifies data produced through clinical trial, biomarker and medical diagnostic studies into an intuitive and user-friendly dashboard. The first of its kind, Trial Insights curates publicly available data nightly from information hubs such as clinicaltrials.gov and customizes it to fit a researcher or research organization’s specific project needs.
Trial Insights, new clinical trial reporting solution, allows researchers to keep track of the evolving landscape of drugs, diseases, sponsors, investigators and medical devices important to their work.
“Trial Insights offers researchers an easy way to navigate the complexity of clinical trials information,” said Ron Ranauro, Founder of Incite Advisors. “Since Trial Insights’ content is digitally curated, researchers can continuously keep track of the evolving landscape of drugs, diseases, sponsors, investigators and medical devices important to their work.”
As the velocity, variety and veracity of data available on sites like clinicaltrials.gov continues to increase, the ability to curate it becomes more valuable to different audiences. With the advancement of personalized medicine, it is important to make the data accessible to the health care and patient communities. Information found on the Trial Insights platform can help guide decision making across the pharmaceutical, biotechnology and contract research organization industries as clinical trial data is a primary information source for competitive intelligence, research planning and clinical study planning.
“We are extremely excited to launch the first Scientist.com exclusive, original service offering to our clients in the life sciences,” said Mark Herbert, Scientist.com Chief Business Officer. “Our goal at Scientist.com is to help cure all diseases by 2050, and we believe solutions like Trial Insights, which greatly simplifies access to and reporting of clinical trial data, will get us one step closer to reaching that goal.”
While screening mammograms aren’t perfect, they are the best way we have right now to detect breast cancer early, when it’s most treatable.
When a screening mammogram shows an abnormal area that looks like a cancer but turns out to be normal, it’s called a false positive. Ultimately the news is good: no breast cancer. But the suspicious area usually requires follow-up with more than one doctor, extra tests, and extra procedures, including a possible biopsy.
A large study suggests that women with false-positive mammogram results have a slightly higher risk of developing invasive breast cancer within the next 10 years.
To do the study, the researchers looked at information from nearly 1.3 million women ages 40 to 70 with no family history of breast cancer who had screening mammograms from 1994 to 2009. The information came from the Breast Cancer Surveillance Consortium database, which is maintained by the National Cancer Institute.
The researchers found that the 1,297,906 women had a total of 2,207,942 screening mammograms. There were:
159,448 false-positive results with a recommendation for more imaging
22,892 false-positive results with a recommendation for biopsy
2,025,602 negative mammograms
Women ages 40 to 49 made up the largest percentage of false-positive mammogram results with a recommendation for more imaging (33.1%). Women with dense breasts also were more likely to have false-positive results.
The researchers then compared the rates of invasive breast cancer between women who had false-positive mammogram results and women who had negative mammogram results:
there were 3.91 invasive breast cancers per 1,000 person-years of follow-up among women with negative mammogram results
there were 5.51 invasive breast cancers per 1,000 person-years of follow-up among women with false-positive mammogram results with a recommendation for more imaging
there were 7.01 invasive breast cancers per 1,000 person-years of follow-up among women with false-positive mammogram results with a recommendation for biopsy
The researchers said the 10-year risk of invasive breast cancer was:
39% higher in women with false-positive results with a recommendation for more imaging
76% higher in women with false-positive results with a recommendation for biopsy
compared to women with negative results.
It’s important to know that the increases above are increases in relative risk — the risk of a woman with a false-positive result relative to the risk of a woman with a negative result.
In terms of absolute risk, the increase is small:
women with false-positive results have about a 2% risk of developing invasive disease in the 10 years after the false-positive result
women with negative results have about a 1% risk of developing invasive disease in the 10 years after the negative result
The researchers didn’t offer an explanation about why false-positive mammogram results appear to be linked to a slightly higher risk of invasive disease. Many experts think that the subtle changes suggested on the mammogram may be an early clue to cancer before actual cancer exists.
It’s also important to know that this association has been suggested in other studies. But the large number of women in the study and the length of follow-up add more evidence that the link between false-positive results and a somewhat higher risk of invasive disease actually exists.
“The power of this study to show the association is very strong, particularly when you combine it with the results of the other studies that have been done,” said Richard Wender, M.D., chief of cancer control at the American Cancer Society, in an interview. “I think we can now say with confidence that women who have had a previous false-positive mammogram are at somewhat higher risk for breast cancer.”
The researchers who did this study want to incorporate false-positive mammogram results into models that predict breast cancer risk.
“Now that we have this information, our hope is that we can add it into existing risk-prediction models to improve their ability to discriminate between women who will go on to develop breast cancer and those who won’t,” said Louise Henderson, Ph.D., of the University of North Carolina Lineberger Comprehensive Cancer Center, who was the lead author of the study. “We should accept that a false-positive mammogram is a risk factor for predicting future risk of breast cancer.
“In clinical terms, that means women who have a false-positive mammogram need to be particularly vigilant about keeping up with regular mammographic screening,” she continued. “The clinicians caring for these women should have a way to track women who have had a false-positive and make sure that every effort is made to keep up to date with mammography.”
It’s important to know that a false-positive mammogram result doesn’t mean you will be diagnosed with breast cancer.
“Having any history of breast biopsies is associated with a higher risk,” said Breastcancer.org President and Founder Marisa Weiss, M.D. “Breast tissue that is dense or has proliferative changes tends to lead to questions on the breast imaging. Sometimes it leads to biopsies. In contrast, breast tissue that is boring, without any extra activity, rarely leads to any kind of biopsy. That kind of inactive breast tissue is less likely to develop breast cancer.”
“This study doesn’t suggest that having a false-positive leads to breast cancer,” said Brian Wojciechowski, M.D., Breastcancer.org’s medical adviser. “Rather, it reflects an association between breast cancer risk and abnormal breast imaging. Women should not worry that getting mammograms will increase their risk of breast cancer in the future.”
There’s only one of you and you deserve the best care possible. Don’t let any obstacles get in the way of your regular screening mammograms, especially if you’ve had a false-positive result.
If you’re worried about cost, talk to your doctor, a local hospital social worker, or staff members at a mammogram center. Ask about free programs in your area.
If you’re having problems scheduling a mammogram, call the National Cancer Institute (800-4-CANCER) or the American College of Radiology (800-227-5463) to find certified mammogram providers near you.
If you find mammograms painful, ask the mammography center staff members how the experience can be as easy and as comfortable as possible for you.
If you’re concerned about unknown results or being called back for more testing, talk to your doctor about what happens when mammogram results are unclear, as well as what to expect if you’re called back for more testing.
For more information on mammograms and other tests to detect and diagnose breast cancer, visit the Breastcancer.org Screening and Testing section.
TSUNAMI in HealthCare under the New Name Verily.com, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)
TSUNAMI in HealthCare under the New Name Verily.com
Curator: Aviva Lev-Ari, PhD, RN
UPDATED on 6/8/2016
The Tricorder project was announced only 3 months after Google entered the life sciences field, according to the report, and came from the same incubator which rolled out the company’s self-driving car and recently cancelled Google Glass.
Verily CEO Andrew Conrad said the scientific basis for the device was proven upon unveiling in 2014, but experts have presented conflicting views on the reality of such a device, STAT Newsreports.
“What (Verily is) really good at is physical measurements — things like temperature, pulse rate, activity level. They are not particularly good at … the chemical and the biological stuff,” Walt toldSTAT news.
Four former Verily employees said the Tricorder “has been seen internally more as a way to generate buzz than as a viable project,” according to the report.
Publicly, Alphabet has said very little about its assortment of companies not named Google.
But internally, Alphabet is a little more forthcoming.
As we reported earlier, Nest CEO Tony Fadell appeared before Google’s all-hands meeting two weeks ago to address recent criticism of his company. During that meeting, Google co-founder and Alphabet exec Sergey Brin also defended another company under the holding conglomerate: Verily, the medical tech unit previously called Google Life Sciences.
Lumped together, Alphabet’s moonshots aren’t making money yet — but Verily is, Brin said.
Verily was the target of a scathing article — in Stat, a medical publication from the Boston Globe — scrutinizing its CEO, Andy Conrad. Several former employees told Stat that Verily suffered a talent exodus due to “derisive and impulsive” leadership by Conrad.
Here’s what Brin said in response at Google’s TGIF meeting:
I have seen a smattering of articles. And, you know, it’s actually sad to see sometimes where it appeared that … former employees or soon-to-be former employees talked to the press. But, anyhow, I can tell you what’s going on with these companies, fortunately. So in Verily’s case, despite a handful of examples, their attrition rate is below Google’s and Alphabet’s as a whole. And also, there are articles that have generally said we are blowing a lot of money and so forth. It’s true that, you know, as whole our Other Bets are not yet profitable, but some of them are, including Verily on a cash basis and increasingly so. So we’re pretty excited about these efforts.
Verily makes money through
partnerships with pharmaceutical companies — such as Novartis, which is licensing and planning to sell Verily’s smart contact lens — and
medical institutions.
It is one of three units contributing to the Other Bets total revenue ($448 million) in 2015, along with
Google Fiber and
Nest.
As we reported earlier, Nest likely brought in around $340 million of that and Fiber pulled close to $100 million, meaning that Verily’s sales were somewhere around $10 million. During the year, all the moonshot units combined reported operating losses of $3.6 billion.
Note Brin’s stipulation that Verily’s profit comes on a “cash basis.” That probably means that it’s not making profit on the normal basis, meaning when you take into account total sales minus total costs. But “cash positive” suggests they’re booking sales faster than they’re spending money, which is a positive sign. Companies normally report financials accounting for all costs. And that’s how Alphabet will next week, when it shares first-quarter results for Google and the Other Bets — although we almost certainly won’t see figures on Verily’s profitability.
We reached out to Alphabet and Verily reps for more clarity, but didn’t get any.
When Google[x] embarked on a project in 2012 to put computing inside a contact lens — an immensely challenging technical problem with an important application to health — we could not have imagined where it would lead us. As a life sciences team within Google[x], we were able to combine the best of our technology heritage with expertise from across many fields. Now, as an independent company, Verily is focused on using technology to better understand health, as well as prevent, detect, and manage disease.
Andy Conrad, Ph.D.
Chief Executive OfficerFormerly the chief scientific officer of LabCorp, Andy is a cell biologist with a doctorate from UCLA. He has always been passionate about early detection and prevention of disease: Andy co-founded the National Genetics Institute, which developed the first cost-effective test to screen for HIV in blood supply.
Brian Otis, Ph.D.
Chief Technical OfficerBrian’s team focuses on end-to-end innovation ranging from integrated circuits to biocompatible materials to sensors. He joined Google[x] as founder of the smart contact lens project and now leads our efforts across all hardware and device projects, including wearables, implanted devices, and technology like Liftware.
Jessica Mega, M.D., MPH
Chief Medical OfficerJessica leads the clinical strategy and research team at Verily. She is a board-certified cardiologist who trained and practiced at Massachusetts General Hospital and Brigham and Women’s Hospital. As a faculty member at Harvard Medical School and a senior investigator with the TIMI Study Group, Jessica directed large, international trials evaluating novel cardiovascular therapies.
Linus Upson
Head of EngineeringA long-time Google software engineer, Linus has been a team lead in developing products that now help billions of people worldwide find the information they need on the Internet, including Chrome and Chrome OS. He now oversees our engineering teams.
Tom Stanis
Head of SoftwareTom spent nine years working on core Google products before joining Google[x] in 2014 to work on the Baseline Study. He now leads all our Software projects, including the development of machine learning algorithms for applications ranging from robotic-assisted surgery to diabetes management.
Vikram (Vik) Bajaj, Ph.D.
Chief Scientific OfficerVik’s broad research interests in industry and as a former academic principal investigator have included structural and systems biology, molecular imaging, nanoscience, and bioinformatics. Vik now leads the Science team in research directions related to our mission.
What are the Dimensions of the Tsumani in Healthcare?
prevention,
detection,
management of disease
Hardware
contact lens with an embedded glucose sensor for measuring the glucose in human tears.
Software
multiple sclerosis, for example, combines wearable sensors with traditional clinical tests
signals that could lead to new knowledge about the disease and why it progresses differently among individuals.
Clinical
Constituencies industry, hospitals, government, academic centers, medical societies, and patient advocacy groups
The Baseline Study is one of these dedicated efforts, a multi-year initiative that aims to identify the traits of a healthy human by closely observing the transition to disease.
Science
Understand processes that lead to conditions like cancer, heart disease, and diabetes
computational systems biology platforms and life sciences tools
bio-molecular nanotechnology for precision diagnostics and therapeutic delivery
advanced imaging methods for applications ranging from early diagnosis to surgical robotics.
2012pharmaceutical
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