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Cambridge Healthtech Institute’s inaugural Cancer Immunotherapy and Combinations meeting will convene immuno-oncology researchers, cancer immunotherapy developers, and technology providers to discuss next-generation approaches and combinations, including small molecule development, to enhance the efficacy of checkpoint inhibitors.
BISPECIFIC ANTIBODIES – DUAL TARGETING
FEATURED PRESENTATION: ANTI-PD1 OR CD137 ENHANCES NK-CELL CYTOTOXICITY TOWARDS CD30+ HODGKIN LYMPHOMA INDUCED BY CD30/CD16A TANDAB AFM13 Martin Treder, Ph.D., CSO, R&D, Affimed
In vivo Efficacy of Bispecific Antibodies Targeting Two Immune-Modulatory Receptors Jacqueline Doody, Ph.D., Vice President, Immunology, F-star Biotechnology, Ltd
Dual-Targeting Bispecific Antibodies for Selective Neutralization of CD47 on Cancer Cells Krzysztof Masternak, Ph.D., Head, Biology, Therapeutic Antibody Discovery, Novimmune
Update on MCLA-134: A Biclonics® Binding Two Immunomodulatory Targets Expressed by T Cells Mark Throsby, Ph.D., CSO, Merus
The ImmTAC Technology: A Cutting-Edge Immunotherapy for Cancer Treatment Samir Hassan, Ph.D., Director, Translational Research & Development, Immunocore Ltd.
RADIOTHERAPY AND CHEMOTHERAPY – PD-1 COMBINATIONS
Rational Development of Combinations of Antiangiogenic Therapy with Immune Checkpoint Blockers Using Mouse Models of HCC and Cirrhosis Dan Duda, D.M.D., Ph.D., Associate Professor, Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School
Harnessing the Immune Microenvironment of Gastrointestinal Cancers Using Combined Modalities Osama Rahma, M.D., Assistant Professor, Internal Medicine/Oncology, University of Virginia
AGONIST – PD-1 AND CTLA-4 COMBINATIONS
The Role of the Target in the Disposition and Immunogenicity of an Anti-GITR Agonist Antibody Enrique Escandón, Ph.D., Senior Principal Scientist, DMPK and Disposition, Merck
Combination of 4-1BB Agonist and PD-1 Antagonist Promotes Antitumor Effector/Memory CD8 T Cells Changyu Wang, Ph.D., Director, Cancer Immunology, Pfizer
Combination Immunotherapy with Checkpoint Blockade, Agonist Anti-OX40 mAb, and Vaccination Rescues Anergic CD8 T Cells William Redmond, Ph.D., Associate Member, Laboratory of Cancer Immunotherapy, Earle A. Chiles Research Institute, Providence Portland Medical Center
Interactive Breakout Discussion Groups with Continental Breakfast
This session features various discussion groups that are led by a moderator/s who ensures focused conversations around the key issues listed. Attendees choose to join a specific group and the small, informal setting facilitates sharing of ideas and active networking. Continental breakfast is available for all participants.
Topic: Small Molecule Targeting of IDO1 and TDO for Cancer Immunotherapy
Moderator: Rogier Buijsman, Ph.D., Head, Chemistry, Netherlands Translational Research Center B.V. (NTRC)
Overcoming challenges of current IDO1 inhibitors lacking selectivity over TDO and having suboptimal drug-like properties
Advances in IDO1 and TDO inhibitor screening
Is selective IDO1 or TDO inhibitors is required, or a dual IDO1/TDO inhibitor is preferred to obtain optimal efficacy and safety in the clinic?
Topic: Strategies for Developing Bispecific Antibodies for Cancer Immunotherapy
Moderator: Krzysztof Masternak, Ph.D., Head, Biology, Therapeutic Antibody Discovery, Novimmune
Considerations for efficacy in vitro and in vivo: selectivity for tumor cells, ADCP, ADCC, in vivo efficacy (xenograft models)
Insights into mechanisms of action
Safety considerations: binding selectivity, PK and tox studies
Topic: Combining Standard Antiangiogenic Therapy with Immune Checkpoint Inhibitors
Moderator: Dan Duda, D.M.D., Ph.D., Associate Professor, Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School
Will checkpoint combination with chemotherapy or other targeted agents prove to have too many toxicity issues?
How do we minimize overlapping toxic effects of radiation and immunotherapy?
How to optimize the sequencing of these two treatment modalities?
SMALL MOLECULE INHIBITORS AS SINGLE AND CHECKPOINT COMBINATION AGENTS
Selective Small Molecule Inhibitors of IDO1 and TDO for Cancer Immunotherapy Rogier Buijsman, Ph.D., Head, Chemistry, Netherlands Translational Research Center B.V. (NTRC)
Potent and Selective Small Molecule USP7 Inhibitors for Cancer Immunotherapy Suresh Kumar, Ph.D., Director, R&D, Progenra, Inc.
Epigenetic Agents for Combination with Cancer Immunotherapy Svetlana Hamm, Ph.D., Head, Biology, Translational Pharmacology, 4SC Group
VACCINES AND CHECKPOINT BLOCKADE IMMUNOTHERAPY
Immunotherapy for Mesothelioma with an in vivo DC Vaccine and PD-1/PD-L1 Blockade Huabiao Chen, M.D., Ph.D., Principal Investigator, Vaccine and Immunotherapy Center, Massachusetts General Hospital
Bringing Together Checkpoint Inhibition with Vaccines Using Customizing Capsids Willie Quinn, Ph.D., President & CEO, Bullet Bio
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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:
Engineers at Washington University in St. Louis found a way to keep a cancerous tumor from growing by using nanoparticles of the main ingredient in common antacid tablets.
The research team, led by Avik Som, an MD/PhD student, and Samuel Achilefu, PhD, professor of radiology and of biochemistry & molecular biophysics in the School of Medicine and of biomedical engineering in the School of Engineering & Applied Science, in collaboration with two labs in the School of Engineering & Applied Science, used two novel methods to create nanoparticles from calcium carbonate that were injected intravenously into a mouse model to treat solid tumors. The compound changed the pH of the tumor environment, from acidic to more alkaline, and kept the cancer from growing.
With this work, researchers showed for the first time that they can modulate pH in solid tumors using intentionally designed nanoparticles. Results of the research were recently published online in Nanoscale.
“Cancer kills because of metastasis,” said Som, who is working on a doctorate in biomedical engineering in addition to a medical degree. “The pH of a tumor has been heavily correlated with metastasis. For a cancer cell to get out of the extracellular matrix, or the cells around it, one of the methods it uses is a decreased pH.”
The researchers set out to find new approaches to raise the pH of the tumor and do so only in the tumor environment. In water, the pH in calcium carbonate increases as high as 9. But when injected into the body, the team discovered that calcium carbonate only raises the pH to 7.4, the normal pH in the human body. However, working with calcium carbonate presented some challenges.
“Calcium carbonate doesn’t like to be small,” Som said. “Calcium carbonate crystals are normally 10 to 1,000 times bigger than an ideal nanoparticle for cancer therapy. On top of that, calcium carbonate in water will constantly try to grow, like stalactites and stalagmites in a cave.”
To solve this issue, Som worked with other researchers in the School of Engineering & Applied Science to create two unique solutions. Teaming up with researchers in the lab of Pratim Biswas, Ph.D., the Lucy & Stanley Lopata Professor and chair of the Department of Energy, Environmental & Chemical Engineering, they developed a method using polyethyleneglycol-based diffusion to synthesize 20- and 300-nanometer-sized calcium carbonate.
Working with Srikanth Singamaneni, Ph.D., assistant professor of materials science, they developed another method to create 100-nanometer-sized calcium carbonate by building on a method known as ethanol-assisted diffusion. By harnessing the complementary expertise of the different labs, the researchers developed a solvent made of albumin to keep the calcium carbonate nanoparticles from growing, allowing them to be injected into the body intravenously.
Commonly, nanoparticles have been made with gold and silver. However, neither are present in the human body, and there are concerns about them accumulating in the body.
“Calcium and carbonate are both found heavily in the body, and they are generally non-toxic,” Som said. “When calcium carbonate dissolves, the carbonate becomes carbon dioxide and is released through the lungs, and calcium is often incorporated into the bones.”
Som and the team injected the calcium carbonate nanoparticles into the mouse fibrosarcoma model daily, which kept the tumor from growing. However, when they stopped injecting the nanoparticles, it started growing again.
Going forward, the researchers plan to determine the optimal dose to prevent metastasis, improve targeting to tumors and determine if it could be used with chemotherapy drugs.
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.”
Epic Sciences’ “no cell left behind” platform can identify circulating tumor cells in an unbiased manner, without enrichment or depletion on any parameter. For example, as indicated in this image, it has been used to detect the AR-V7-positive cells among the cells collected in a simple blood draw. The AR-V7 splice variant is linked to resistance of androgen receptor-targeting drugs in metastatic castration-resistant prostate cancer patients.
Just as signposts provide information, direction, and guidance, so too cancer biomarkers can better reveal the complex, dynamic, and heterogeneous landscape of malignancies.
Such information is critical for creating better cancer diagnostics, prognostics, and therapeutics, but the journey to find just the right biomarker is often a long and winding road.
Biomarker discovery and utilization is being explored by means of various methods and technologies. These include the isolation and characterization of rare circulating cancer cells, the use of multiplexing to extract information from limited amounts of sample, and even the application of evolutionary biology to detect early cell changes.
These approaches are all being developed by companies interested in improving cancer diagnostics, prognostics, and therapeutics. For example, one of the companies cited in this article is scrutinizing circulating tumor cells (CTCs) to predict resistance to cancer drugs. (This work was presented at a scientific retreat convened by the Prostate Cancer Foundation.) Other companies represented in this article are developing novel cancer diagnostic approaches. (These were detailed at the recent Cambridge Health Diagnostics Summit.)
While a typical blood sample from a cancer patient can contain 30 million nucleated cells, it’s estimated that perhaps only 5 of those cells may be destined to form tumors. “Most present-day diagnostic technologies cannot precisely detect those rare CTCs,” observed Ryan Dittamore, vice president, translational research and clinical affairs, Epic Sciences. “Identifying robust predictive biomarkers that can be utilized in real-time with a test compatible with diagnostic workflows is one of the greatest challenges to precision medicine.
“Epic Sciences is focused on developing sensitive diagnostic tests to characterize CTCs molecularly in order to match therapies to a patient’s cancer biology.” As Dittamore indicated at the Prostate Cancer Foundation event, the company evaluated its CTC approach in a study undertaken with Howard Scher, M.D., chief of the genitourinary oncology service at Memorial Sloan Kettering.
“We focused on a form of prostate cancer called metastatic castration-resistant prostate cancer,” explained Dittamore. “In the study, we confirmed the value of the prostatic cancer biomarker AR-V7 in 193 patient samples. In men with this androgen receptor (AR) splice variant, treatment with taxanes may be more effective than treatment with AR-signaling-directed agents (enzalutamide or abiraterone).”
In Epic Sciences’ “no cell left behindTM” approach, all nucleated cells from a blood sample are placed on a slide. CTCs are stained using biomarker monoclonal antibodies and assessed via immunofluorescence and high-resolution digital pathology scanning.
“We’ve industrialized this process,” asserted Dittamore, “and can evaluate millions of patient cells in every assay. Once identified, we can then isolate individual CTCs for further single-cell evaluation, such as with next-generation sequencing.” Overall, the company’s approach can achieve the following tasks: quantifying the number of cancer cells, characterizing biomarker expression (specifying, for example, subcellular localization and genomic alterations), and assessing disease heterogeneity and clonality of cancer cell types.
Commercializating the tests will come later, indicated Dittamore. “We will continue refining and expanding tests with our numerous collaborators in academia and pharma, many of whom are using our biorepository capabilities to bank samples for later study of biomarkers for other types of cancer.
The ultimate goal of molecular diagnostics is to get as much information as possible, as quickly as possible, with as little sample as possible. Unfortunately, it is often necessary to make do with samples that are limited in number and extent—consider, for example, formalin-fixed, paraffin-embedded (FFPE) specimens—even though one would like to extract comprehensive information. To help solve this problem, Qiagen has developed a new platform that marries and automates two proven techniques: multiplex PCR and capillary electrophoresis.
“We created a novel and automated clinical platform called Modaplex for real-time sampling, size separation of PCR products, amplification curve building, and Ct (cycle threshold) calculations,” summarized Lilly Kong, DVM, Qiagen’s senior director, assay development. “As a result, from a very limited amount of sample, we can utilize a multimodal, multiplex, essentially ‘all in one well’ means to quickly obtain actionable results.”
Dr. Kong said that Qiagen has developed multiple oncological biomarker tests including RAS, cMET, FGFR, Cell Cycle, and DLBCL signatures. “We can multiplex up to 40 targets in a single reaction,” she asserted. “Traditional assays allow testing of only one or a few assays at a time. Further, this is an architecture that uses a modular approach.”
Dr. Kong described development of an assay evaluating cMET and epidermal growth factor receptor (EGFR) expression and copy number variation. These two players are important because the MET proto-oncogene encodes for the receptor tyrosine kinase, cMET, which is widely expressed by many cells.
Under pathological conditions, cMET confers survival and invasive properties of cancer cells while potentially blocking EGFR therapies. “This multimodal 21-plex assay,” Dr. Kong indicated, “succeeded in evaluateing nine mRNA targets and nine genomic DNA targets with appropriate standards and external process controls.”
Qiagen also examined cMET simple nucleotide polymorphisms (SNPs) in a 16-plex reaction tube. “The modular approach enables combinations of important biomarker assays that can test for disparate target types, such as SNPs, expression biomarkers, miRNAs, and fusion genes,” Dr. Kong detailed. “Further, one FFPE slide is sufficient for about 10 assays with 10–50 ng input per reaction. The automation is user-friendly while sensitivity, specificity, and precision are equal to or exceed singleplex assays.”
Although Modaplex started with oncological applications, many other panels are in development. For example, Qiagen is working on pathogen detection applications as well as in-process monitoring applications for biologicals manufacturing.
AstraZeneca’s WEE1 protein inhibitor AZD1775 Shows Success Against Tumors with a SETD2 mutation
Stephen J. Williams, Ph.D., Curator
There have been multiple trials investigating the utility of cyclin inhibitors as anti-tumoral agents (see post) with the idea of blocking mitotic entry however another potential antitumoral mechanism has been to drive the cell into mitosis in the presence of DNA damage or a defective DNA damage repair capacity. A recent trial investigating an inhibitor or the cell cycle checkpoint inhibitor Wee1 showed positive results in select cohorts of patients with mutations in DNA repair, indicating the therapeutic advantage of hijacking the cell’s own DNA damage response, much like how PARP inhibitor Olaparib works in BRCA1 mutation positive ovarian cancer patients.
Investigators at Oxford University say that one of AstraZeneca’s ($AZN) pipeline drugs proved particularly effective in killing cancer cells with a particular genetic mutation.
The ex-Merck ($MRK) drug is AstraZeneca’s WEE1 protein inhibitor AZD1775, which proved particularly lethal to genes with a SETD2 mutation, which the researchers see as a potential ‘Achilles heel’ often found in kidney cancer and childhood brain tumors.
“When WEE1 was inhibited in cells with a SETD2 mutation, the levels of deoxynucleotides, the components that make DNA, dropped below the critical level needed for replication,” noted Oxford’s Andy Ryan. “Starved of these building blocks, the cells die. Importantly, normal cells in the body do not have SETD2 mutations, so these effects of WEE1 inhibition are potentially very selective to cancer cells.”
AstraZeneca landed rights to the drug back in 2013, when incoming Merck R&D chief Roger Perlmutter opted to spin it out while focusing an immense effort around the development of its PD-1 checkpoint inhibitor KEYTRUDA® (pembrolizumab). Since then, AstraZeneca has made it available to academic investigators through their open innovation program.
Wee1, DNA damage checkpoint and cell cycle regulation
In fission yeast, Wee1 delays entry into mitosis by inhibiting the activity of Cdk1, the cyclin-dependent kinase that promotes entry into mitosis (Cdk1 is encoded by the cdc2+ gene in fission yeast and the CDC28 gene in budding yeast) (Russell and Nurse, 1987a). Wee1 inhibits Cdk1 by phosphorylating a highly conserved tyrosine residue at the N-terminus (Featherstone and Russell, 1991; Gould and Nurse, 1989; Lundgren et al., 1991; Parker et al., 1992; Parker and Piwnica-Worms, 1992). The phosphatase Cdc25 promotes entry into mitosis by removing the inhibitory phosphorylation (Dunphy and Kumagai, 1991; Gautier et al., 1991; Kumagai and Dunphy, 1991; Millar et al., 1991; Russell and Nurse, 1986; Strausfeld et al., 1991). Loss of Wee1 activity causes cells to enter mitosis before sufficient growth has occurred and cytokinesis therefore produces two abnormally small daughter cells (Fig. 1A) (Nurse, 1975). Conversely, increasing the gene dosage of wee1 causes delayed entry into mitosis and an increase in cell size, indicating that the levels of Wee1 activity determine the timing of entry into mitosis and can have strong effects on cell size (Russell and Nurse, 1987a). Similarly, cdc25– mutants undergo delayed entry into mitosis, producing abnormally large cells, and an increase in the gene dosage of cdc25 causes premature entry into mitosis and decreased cell size (Russell and Nurse, 1986). Despite these difficulties, early work in fission yeast suggested that the Wee1 kinase plays an important role in a checkpoint that coordinates cell growth and cell division at the G2/M transition (Fantes and Nurse, 1978; Nurse, 1975; Thuriaux et al., 1978). WEE1 is an evolutionarily conserved nuclear tyrosine kinase (Table 2) that is markedly active during the S/G2 phase of the cell cycle [24, 25]. It was first discovered 25 years ago as a cell division cycle (cdc) mutant-wee1– in the fission yeast, Schizosaccharomyces pombe [26]. Fission yeast lacking WEE1 are characterized by a smaller cell size, and this phenotype has been attributed to the ability of WEE1 to negatively regulate the activity of cyclin dependent kinase, Cdc2 (Cdc28 in budding yeast and CDK1 in human), in the Cdc2/CyclinB complex [27]. Recently, WEE1 was shown to directly phosphorylate the mammalian core histone H2B at tyrosine 37 in a cell cycle dependent manner. Inhibition of WEE1 kinase activity either by a specific inhibitor (MK-1775) or suppression of its expression by RNA interference abrogated H2B Y37-phosphorylation with a concurrent increase in histone transcription [17].
As shown in the Below figure Wee1 is a CDK cyclin kinase which results in an inactivating phosphorylation event on CDK/Cyclin complexes
Figure 1. Schematic representation of the effects of Chk1 and Wee1 inhibition on CDK-CYCLIN complex regulation, that gets more activated being unphosphorylated from Cell cycle, checkpoints and cancer by Laura Carrassa.
Figure 2. Schematic representation of the role of Chk1 and Wee1 in regulation of the CDK-cyclin complexes involved in S phase and M phase entry from Cell cycle, checkpoints and cancer by Laura Carrassa.
The following articles discuss how Wee1 can be a target and synergize with current chemotherapy
p53 mutation Frequency in Ovarian Cancer and contribution to chemo-resistance
The following is from the curated database TCGA and cBioPortal TCGA Data Viewer for mutations found in ovarian cancer sequencing studies in the literature
Confirmed that mutations in gene TP53 are present in more than 96 percent of ovarian cases (>57% mutation frequency) while SETD2 mutations are present in only 1% of cases (1.1% mutation frequency).
In general, ovarian cancers with TP53 are considered to have increased resistance to commonly used cytotoxic agents used for this neoplasm, for example cisplatin and taxol, as TP53 is a major tumor suppressor/transcription factor involved in cell cycle, DNA damage response, and other chemosensitivity mechanisms. One subtype of TP53 mutations, widely termed gain-of-function (GOF) mutations, surprisingly converts this protein from a tumor suppressor to an oncogene. We term the resulting change an oncomorphism. In this review, we discuss particular TP53 mutations, including known oncomorphic properties of the resulting mutant p53 proteins. For example, several different oncomorphic mutations have been reported, but each mutation acts in a distinct manner and has a different effect on tumor progression and chemoresistance.
Figure 1. The spectrum of protection against cancer provided by WT p53. As copies of WT p53 (TP53+/+) are lost, cancer protection decreases. When oncomorphic mutations are acquired, cancer susceptibility is increased.
Oncomorphic p53 proteins were first identified over two decades ago, when different TP53 mutants were introduced into cells devoid of endogenous p53 [38,39]. Among all cancers, the most common oncomorphic mutations are at positions R248, R273, and R175, and in ovarian cancers the most common oncomorphic TP53 mutations are at positions R273, R248, R175, and Y220 at frequencies of 8.13%, 6.02%, 5.53%, and 3.74%, respectively [33,34]. In in vitro studies, cells with oncomorphic p53 demonstrate increased invasion, migration, angiogenesis, survival, and proliferation as well as resistance to chemotherapy [35,37,40,41].
Figure 2. Hotspots for TP53 mutations. Mutations that occur at a frequency greater than 3% are highlighted. Certain p53 mutants have oncomorphic activity (denoted by *), functioning through novel protein interactions as well as novel transcriptional targets to promote cell survival and potentially chemoresistance. Codons in the “other” category include those that produce non-functional p53 or have not been characterized to date.
Osman AA, Monroe MM, Ortega Alves MV, Patel AA, Katsonis P, Fitzgerald AL, Neskey DM, Frederick MJ, Woo SH, Caulin C, Hsu TK, McDonald TO, Kimmel M, Meyn RE, Lichtarge O, Myers JN.
Mol Cancer Ther. 2015 Feb;14(2):608-19. doi: 10.1158/1535-7163.MCT-14-0735-T. Epub 2014 Dec 10.
Mol Cancer Ther. 2015 Jan;14(1):90-100. doi: 10.1158/1535-7163.MCT-14-0496. Epub 2014 Nov 5.
Mol Cancer Ther. 2013 Aug;12(8):1442-52. doi: 10.1158/1535-7163.MCT-13-0025. Epub 2013 May 22.
1Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
2Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
3Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland.
4Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. mgottesman@nih.gov.
Abstract
Despite early positive response to platinum-based chemotherapy, the majority of ovarian carcinomas develop resistance and progress to fatal disease. Protein phosphatase 2A (PP2A) is a ubiquitous phosphatase involved in the regulation of DNA-damage response (DDR) and cell-cycle checkpoint pathways. Recent studies have shown that LB100, a small-molecule inhibitor of PP2A, sensitizes cancer cells to radiation-mediated DNA damage. We hypothesized that LB100 could sensitize ovarian cancer cells to cisplatin treatment. We performed in vitro studies in SKOV-3, OVCAR-8, and PEO1, -4, and -6 ovarian cancer lines to assess cytotoxicity potentiation, cell-death mechanism(s), cell-cycle regulation, and DDR signaling. In vivo studies were conducted in an intraperitoneal metastatic mouse model using SKOV-3/f-Luc cells. LB100 sensitized ovarian carcinoma lines to cisplatin-mediated cell death. Sensitization via LB100 was mediated by abrogation of cell-cycle arrest induced by cisplatin. Loss of the cisplatin-induced checkpoint correlated with decreased Wee1 expression, increased cdc2 activation, and increased mitotic entry (p-histone H3). LB100 also induced constitutive hyperphosphorylation of DDR proteins (BRCA1, Chk2, and γH2AX), altered the chronology and persistence of JNK activation, and modulated the expression of 14-3-3 binding sites. In vivo, cisplatin sensitization via LB100 significantly enhanced tumor growth inhibition and prevented disease progression after treatment cessation. Our results suggest that LB100 sensitizes ovarian cancer cells to cisplatin in vitro and in vivo by modulation of the DDR pathway and cell-cycle checkpoint abrogation.
So Why SETD2 Mutations?
SETD2 is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active chromatin and chromatin remodeling.
Kanu N, Grönroos E, Martinez P, Burrell RA, Yi Goh X, Bartkova J, Maya-Mendoza A, Mistrík M, Rowan AJ, Patel H, Rabinowitz A, East P, Wilson G, Santos CR, McGranahan N, Gulati S, Gerlinger M, Birkbak NJ, Joshi T, Alexandrov LB, Stratton MR, Powles T, Matthews N, Bates PA, Stewart A, Szallasi Z, Larkin J, Bartek J, Swanton C.
Oncogene. 2015 Mar 2. doi: 10.1038/onc.2015.24. [Epub ahead of print]
Ahn JW, Kim HS, Yoon JK, Jang H, Han SM, Eun S, Shim HS, Kim HJ, Kim DJ, Lee JG, Lee CY, Bae MK, Chung KY, Jung JY, Kim EY, Kim SK, Chang J, Kim HR, Kim JH, Lee MG, Cho BC, Lee JH, Bang D.
Genome Med. 2014 Feb 27;6(2):18. doi: 10.1186/gm535. eCollection 2014.
#2. Gemcitabine Hydrochloride With or Without WEE1 Inhibitor MK-1775 in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
This randomized phase II clinical trial studies how well gemcitabine hydrochloride and WEE1 inhibitor MK-1775 work compared to gemcitabine hydrochloride alone in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that has come back after a period of time. Gemcitabine hydrochloride may prevent tumor cells from multiplying by damaging their deoxyribonucleic acid (DNA, molecules that contain instructions for the proper development and functioning of cells), which in turn stops the tumor from growing. The protein WEE1 may help to repair the damaged tumor cells, so the tumor continues to grow. WEE1 inhibitor MK-1775 may block the WEE1 protein activity and may increase the effectiveness of gemcitabine hydrochloride by preventing the WEE1 protein from repairing damaged tumor cells without causing harm to normal cells. It is not yet known whether gemcitabine hydrochloride with or without WEE1 inhibitor MK-1775 may be an effective treatment for recurrent ovarian, primary peritoneal, or fallopian tube cancer.
Primary Outcome Measures:
PFS evaluated using RECIST version 1.1 [ Time Frame: Time from start of treatment to time to progression or death, whichever occurs first, assessed up to 1 year ] [ Designated as safety issue: No ]
Secondary Outcome Measures:
GCIG CA125 response rate [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
Incidence of grade 3 or 4 serious adverse events, graded according to the National Cancer Institute CTCAE version 4.0 [ Time Frame: Up to 1 year ] [ Designated as safety issue: Yes ]
Objective response by RECIST version 1.1 [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
Overall survival [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
Survival estimates will be computed using the Kaplan-Meier method.
p53 protein expression in archival tumor tissue by immunohistochemistry (IHC) [ Time Frame: Baseline ] [ Designated as safety issue: No ]
TP53 mutations (presence and type of mutation) by Sanger sequencing [ Time Frame: Baseline ] [ Designated as safety issue: No ]
These Trials Are Not Investigating TP53 Status of Patient Cohorts
To establish the safety and tolerability of single-agent MK-1775 in patients with refractory solid tumors
To determine the pharmacokinetics of MK-1775 in patients with refractory solid tumors
SECONDARY OBJECTIVES:
To determine the effect of MK-1775 on markers of DNA damage and apoptosis in tumor tissue and circulating tumor cells
To evaluate the antitumor activity of MK-1775 in patients with refractory solid tumors
Note: A further expansion cohort of 6 additional patients with documented tumors harboring BRCA-1 or -2 mutations will lso be enrolled at the MTD to further explore the safety of the agent and obtain preliminary evidence of activity in this patient population
To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose of MK-1775 (WEE1 inhibitor MK-1775) administered on days 1 through 5 every 21 days, in combination with oral irinotecan (irinotecan hydrochloride), to children with recurrent or refractory solid tumors.
To define and describe the toxicities of MK-1775 in combination with oral irinotecan administered on this schedule.
III. To characterize the pharmacokinetics of MK-1775 in children with refractory cancer.
SECONDARY OBJECTIVES:
To preliminarily define the antitumor activity of MK-1775 and irinotecan within the confines of a Phase 1 study.
To obtain initial Phase 2 efficacy data on the anti-tumor activity of MK-1775 in combination with irinotecan administered to children with relapsed or refractory neuroblastoma and in children with relapsed or refractory medulloblastoma/CNS PNET (central nervous system primitive neuroectodermal tumor).
III. To investigate checkpoint over-ride by MK-1775 via the mechanism-based pharmacodynamic (PD) biomarker of decreased cyclin-dependent kinase 1 (CDK1) phosphorylation in correlative and exploratory studies.
To evaluate potential predictive biomarkers of MK-1775 sensitivity, including v-myc avian myelocytomatosis viral oncogene homolog (MYC), v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), phosphorylated-WEE1 G2 checkpoint kinase (p-Wee1), enhancer of zeste homolog 2 (Drosophila) (EZH2) and gamma-H2A histone family, member X (H2AX) in tumor tissues in correlative and exploratory studies.
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
Given the following speakers, this event will have a large focus on use of cancer immunotherapy as well as new targets in the precision medicine arena.
Register today: Philly.com/CancerEvent – Use the promo code “AACR” for discounted $45 tickets.
The genetic tests help refine diagnoses with greater precision than standard imaging tests and blood work by spotting known mutations that can inform the treatment plan. Since it launched in February 2013, the CPD has performed more than 4,000 advanced diagnostics, representing a wide range of cancers. It’s also producing actionable findings: Of those tests, 75 percent found disease-associated mutations, revealing possible new treatment pathways.
ACC’s role as a national leader in personalized cancer care was also reinforced with the opening of the Center for Rare Cancers and Personalized Therapy in 2015.
Directed by Marcia Brose, MD, PhD, this virtual center enrolls patients into clinical trials based on genetic markers rather than tumor origin. Patients with the same mutation, BRAF for instance, but different cancers, are part of the same clinical study investigating a targeted therapy. A story, set to air on TV news affiliates across the country in the upcoming weeks, will feature a patient with a rare salivary tumor who ran out of treatment options, until a HRAS mutation identified through the CPD put him back on track, after switching to the drug tipifarnib. The patient responded well, and a recent scan revealed that his disease has stabilized.
“Philadelphia is a hotbed for healthcare innovation and groundbreaking scientific research—which becomes even more apparent as the ACC continues to move the needle in the precision medicine world,”Abramson Cancer Center (ACC) director Chi Van Dang, MD, PhD, said. “Quickly evolving diagnostics and genetic tests, cancer vaccines, and powerful personalized therapies that use the body’s own immune system to fight off cancer: These are just a few of the medical advances being utilized today that are giving patients the greatest chance.”
For Media Inquiries see the following AACR contact information:
Julia Gunther
Assistant Director, Media and Public Relations
215-446-6896
Cell: 267-250-5441
Fax: 215-861-5937 julia.gunther@aacr.org
Gunther promotes the AACR’s meetings, journals, and initiatives to the media and the public.
Lauren Walens Senior Manager, Media and Public Relations
215-446-7163
Fax: 267-765-1050 lauren.walens@aacr.org
Walens promotes the AACR’s meetings, journals, and initiatives to the media and the public. She also manages the AACR’s blog, Cancer Research Catalyst.
Lauren Riley
Senior Coordinator, Media and Public Relations
215-446-7155
Fax: 215-446-7291 lauren.riley@aacr.org
Riley is responsible for media relations promotion and support, conference newsroom logistics, writing and proofreading, website and news release copy, as well as office support for the Communications and Public Relations Department staff.
Will President Obama’ s Cancer Immunotherapy Colloquium (dubbed Moonshot) mean Government is Fully Behind the War on Cancer or have we heard this before?
UPDATED on 12/13/2016
Greg Simon, White House Cancer Moonshot Task Force: Interview Q&A
The following is an interview recently conducted by PMWC with Greg Simon, Executive Director at the White House Cancer Moonshot Task Force. The discussion focused on the future of the Cancer Moonshot with the upcoming change of administration.
A status update on the Cancer Moonshot will be presented at the upcoming Precision Medicine World Conference (PMWC) 2017 Silicon Valley. To register, click here.
Subject: PMWC News – Late Breaking Interview – The White House Cancer Moonshot in Limbo
Reporter: Stephen J. Williams, Ph.D
President Obama announces a “Moonshot” Program to create collaborations aimed at developing immunotherapies to cure cancer by 2020 at his last State of the Union Address. Vice President Biden will lead the effort.
President Barack Obama announced a moonshot aimed at curing cancer, a project to be led by Vice President Joe Biden.
The United States can do “so much more,” Obama said in his seventh and final State of the Union address Jan. 12. “Last year, Vice President Biden said that with a new moonshot, America can cure cancer. Last month, he worked with this Congress to give scientists at the National Institutes of Health the strongest resources they’ve had over a decade.
“Tonight, I’m announcing a new national effort to get it done. And because he’s gone to the mat for all of us, on so many issues over the past 40 years, I’m putting Joe in charge of mission control. For the loved ones we’ve all lost, for the family we can still save—let’s make America the country that cures cancer once and for all.”
Did Patrick Soon-Shiong attempt to scoop President Barack Obama’s State of the Union address?
Several days before Obama announced the federal government’s moonshot to cure cancer, Soon-Shiong put out a draft press release, claiming that the White House, NIH, FDA and pharmaceutical companies have united in “Cancer MoonShot 2020,” an immunotherapy clinical trials program he devised.
Soon-Shiong, founder and CEO of NantWorks and the Chan Soon-Shiong Institute of Molecular Medicine, ultimately announced his moonshot on Jan. 11, a day before Obama announced his.
Government agencies said the biotechnology billionaire Patrick Soon-Shiong had overstated the extent of their involvement in “Cancer MoonShot 2020,” the immunotherapy clinical trials program he put together.
In an in-depth conversation with Matthew Bin Han Ong, a reporter with The Cancer Letter, Soon-Shiong said that while his program doesn’t seek federal funds, it has the support of NCI and FDA officials.
Soon-Shiong said he and Vice President Joe Biden met to discuss their interlocking missions and are now pursuing them.
PHILADELPHIA — The American Association for Cancer Research (AACR) applauds and commends President Obama and Vice President Biden for their dedication in the fight against cancer discussed during tonight’s State of the Union address.
The AACR looks forward to working with the administration and Congress to make faster progress against cancer so that we might achieve the goal that Vice President Biden outlined during his speech in the Rose Garden Oct. 21, 2015, specifically that now is the time to make an “absolute national commitment to end cancer as we know it today.”
“We have indeed reached an inflection point, where the number of discoveries that are being made at such an accelerated pace are saving lives and bringing enormous hope for cancer patients, even those with advanced disease,” said AACR President José Baselga, MD, PhD, physician-in-chief and chief medical officer at Memorial Sloan Kettering Cancer Center. “Now is the time for a major new initiative in cancer science that supports and builds upon our basic science foundation while translating these exciting scientific discoveries into improved treatments for cancer patients, such as in the areas of genomics, precision medicine, and immuno-oncology. Tonight’s State of the Union address underscores the importance of collaborations if we are to achieve the vision that President Obama has outlined.”
To that end, on Jan. 8, a group of 15 AACR members, led by Baselga and comprising a number of AACR Board Members, and other AACR leaders from nine states and 10 of the top cancer centers and medical institutions in the U.S., met with Vice President Biden’s senior staff to discuss the state of cancer research, as well as Vice President Biden’s commitment to leading in this important issue.
US Vice President Biden will meet with University of Pennsylvania researchers to discuss the new Moonshot program to eliminate cancer. Photo from http://www.philly.com
WASHINGTON – Vice President Biden will launch his effort to find a cure for cancer Friday in Philadelphia, with a visit to Penn’s Abramson Cancer Center at the school’s Perelman School of Medicine.
Biden announced the visit in an online post Tuesday night, when the call to cure the disease was one of the highlights of President Obama’s State of the Union speech.
“It’s personal for me. But it’s also personal for nearly every American, and millions of people around the world,” said Biden’s post on Medium. The vice president’s son Beau died of brain cancer at the age of 46 last year.
Biden compared the effort to President Kennedy’s call to go to the moon.
Vice President Biden is scheduled to spend part of Friday afternoon at the University of Pennsylvania’s Abramson Cancer Center, the first stop on his quest for the United States to cure cancer. President Obama announced the new “Moon Shot” mission during his State of the Union address Tuesday night, comparing it with John F. Kennedy’s 1961 declaration to Congress that the nation would land a man on the moon by the end of the decade.Biden’s 3 p.m. visit includes a tour of laboratories and a roundtable discussion with researchers at the Smilow Center for Translational Research and the Perelman Center for Advanced Medicine, both 3400 Civic Center Blvd. The events are not open to the public but are likely to cause some disruption.
In an internal e-mail Thursday afternoon, Garry Scheib, CEO of the Hospital of the University of Pennsylvania, told employees that parts of the building would be emptied for security reasons from 11 a.m. through evening. “In addition, the Secret Service will temporarily close roadways near our campus to allow for secure transport of the Vice President,” Scheib wrote.
A billionaire medical entrepreneur has pulled together several drugmakers and Philadelphia-based Independence Blue Cross to speed development of what researchers hope could be a powerful weapon against cancers – potent combinations of new drugs that harness the body’s immune system.
So-called immunotherapies help disease-fighting cells attack tumors. Yet researchers believe they may work best when two, three, or more of the drugs are used together – overwhelming a tumor’s cellular defenses with attacks from all sides.
The group – called the National Immunotherapy Coalition – brought together by Patrick Soon-Shiong calls itself Moon Shot 2020. The name spun out of conversations Soon-Shiong had last year with Vice President Biden, whose son Beau died of cancer in May. In his October announcement that he was not running for president, Biden suggested a project of moon-shot proportions would be needed to defeat cancer.
A controversial figure in oncology research circles because of his self-promotion, Soon-Shiong made his fortune by inventing the cancer drug Abraxane in the early 1990s. California-based Amgen and New Jersey-based Celgene have joined the effort. Early reports suggested Pfizer, Merck, and GlaxoSmithKline might participate, but other reports indicated they had not as of Monday.
Independence Blue Cross said in a statement Monday that it entered into an agreement with NantHealth, one of Soon-Shiong’s companies, to cover next-generation whole genome sequencing, which is a test designed to detect gene mutations that may serve as markers to help doctors choose cancer treatment.
Independence said its agreement with NantHealth involves a “very specific and complex lab study” related to certain types of cancer. The test will be covered for members with “specific conditions including rare cancers, tumors in children, metastatic cancer of unknown primary, primary brain cancer, triple negative breast cancer, and metastatic cancer where conventional therapies have been exhausted and patients remain candidates for further therapy. Coverage for the testing will be available to eligible members of Independence commercial plans in March 2016.”
As for the National Immunotherapy Coalition, Independence said members referred by their oncologist for participation in one of the approved Moon Shot 2020 clinical trials will be eligible for coverage for the routine patient care costs related to the trial. The coverage includes all routine services required for the patient – such as blood tests, supportive medications, and surgical interventions.
“Independence Blue Cross is committed to bringing state-of-the-art advances in oncology to our members and making care accessible and affordable,” Daniel J. Hilferty, president and CEO, Independence Blue Cross, said in the statement. “Decisions around cancer care are complex and personal. We’re focused on supporting Independence members and their oncologists by offering coverage for this innovative approach to treating cancer. Whole genome sequencing is one more option to help inform a personalized, effective treatment plan.”
Read more at http://www.philly.com/philly/business/20160112_Billionaire_pulls_together_drugmakers__IBX_for_cancer_collaboration.html#XuXeFCydClgRsX0W.99
This is a Great Announcement But What is the History of the Government and THE WAR on CANCER? (Have we heard this before?)
The War on Cancer (launced by US President Nixon in the early 1970’s) has been discussed on this site from a historical perspective
A summation of these efforts would say we have achieved great results in reducing the burden of cancer (through smoking cessation, early screening programs, better education, as well as therapeutic advances) however as the worldwide populace ages we are, and will see, a “rising tidal wave” of cancer incidence across the globe, and cancer researchers are feeling we are at an important precipice on this war, one which could be lost.
And the program which both President Obama and Vice President Biden are suggesting, the power would be a massive collaboration between government, academia, industry, and patient advocacy will certainly produce positive results.
However these efforts have been ongoing as with the University of Pennsylvania-Novartis deal to work together on CAR-T therapies for leukemias as well as other cancers
In 2003 then NCI president Dr. Andrew C. von Eschenbach announced, after discussions with leaders in the field, that
“I have proposed a challenge goal for the field of cancer research- to eliminate suffering and death due to cancer by 2015. I issued this challenge because I believe we are at a ‘strategic inflection’ in oncology…”
Later in early decade of 2010 another program began to help make a push to recoup some of the government research $ lost to budgetary constraints on the NIH
This program has met much success in raising money, awareness, and clinical trial enrollment (following shows current stats from the organization site)
Founded: May 28, 2008
Funds Pledged since inception: Over $370 Million
Number of scientists participating in SU2C-funded research: Over 1000
Clinical Trails funded by SU2C planned, initiated or completed: Over 160
Patients enrolled in SU2C supported Clinical Trials: Over 6,000 patients
Number of institutions joining in SU2C’s collaborative mission: 129
However, although it has grown the cancer research world encompasses a greater number than they can provide for.
In short, there has been no government effort much like Nixon’s War on Cancer, which took an obscure disease at the time and not only put it in the limelight but probably the most powerful result was the creation of the National Cancer Institute, thereby developing a framework to promote cancer research for the next century. President Obama should be applauded for this effort yet the real test for the Moonshot program will be to create, much like the NCI did, a self-perpetuating system by which continued further advancement can be made.
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