Welcome to the first of several sections to be featured this year in DDNews with an eye on cancer research news. The topic, of course, isn’t a new one for us. Oncology is one of the single most common topics on which our news stories focus, and we have an entire website devoted to the topic at www.ddncancer.com that runs parallel to our site at www.ddn-news.com.
With so much to cover, we decided to run four “Special Focus” sections on cancer research this year, debuting with this one and then showing up again in the July, October and December issues. How they will shape up in the months to come largely depends on what news is out there at the time, but some might have specific topic focuses, such as we did with the Special Focus on Cancer in the September 2016 issue of DDNews that looked solely at immuno-oncology.
In this section, you’ll find stories from specific institutions and companies that touch on cancer research, but before we get to those, we wanted to give you a broader look at a few issues pertinent to the oncology scene: reproducibility, genomics data availability and promising locations to conduct research.
The issue of reproducibility
This topic is particularly timely with the growing concerns in general about difficulties in getting the same results from the same samples, labs or similar studies. In fact, in this February 2017 issue our bimonthly contributor Peter Kissinger talks about that very issue (though not in regards to cancer specifically) in the column “The irreproducibility of published science.”
But dovetailing with that came some thoughts from a representative of Bio-Rad Laboratories who contacted us regarding a study published in December in Analytical Chemistry that demonstrated inter-lab reproducibility for the measurement of an important genetic marker for guiding therapy of certain cancers. This marker is challenging to quantify reproducibly using quantitative PCR (qPCR) or next-generation sequencing (NGS), but a number of laboratories were able to quantify the marker with similar results in all samples using digital PCR—Bio-Rad, as you might imagine, was the maker of the digital PCR technology used for the study.
As the representative noted, “this finding is in stark contrast to a recent JAMA Oncology article that reported wildly different gene sequencing results between two different commercially available tests.”
In the Analytical Chemistry study, titled “International Interlaboratory Digital PCR Study Demonstrating High Reproducibility for the Measurement of a Rare Sequence Variant,” the researcher set out to test the claim that digital PCR (dPCR) can offer highly reproducible quantitative measurements in disparate laboratories. Twenty-one laboratories measured four blinded samples containing different quantities of a KRAS fragment encoding G12D, an important genetic marker for guiding therapy of certain cancers.
As for why this marker is challenging to quantify reproducibly using qPCR or NGS, that is because of the presence of competing wild type sequences and the need for calibration. Using dPCR, however, 18 laboratories were able to quantify the G12D marker within 12 percent of each other in all samples, the authors notes, adding, “Three laboratories appeared to measure consistently outlying results; however, proper application of a follow-up analysis recommendation rectified their data. Our findings show that dPCR has demonstrable reproducibility across a large number of laboratories without calibration. This could enable the reproducible application of molecular stratification to guide therapy and, potentially, for molecular diagnostics.”
The JAMA Oncology article that found some problems with irreproducibility focused on NGS systems and was titled “Comparison of 2 Commercially Available Next-Generation Sequencing Platforms in Oncology.
Access to genomic data
In early January, the American Association for Cancer Research (AACR) announced the first public release of cancer genomic data aggregated through its initiative known as AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE). The data set includes nearly 19,000 de-identified genomic records collected from patients who were treated at eight international institutions, reportedly making it among the largest fully public cancer genomic data sets released to date.
The release includes data for 59 major cancer types, including data on nearly 3,000 patients with lung cancer, more than 2,000 patients with breast cancer, and more than 2,000 patients with colorectal cancer. The genomic data and a limited amount of linked clinical data for each patient can be accessed via the AACR website or downloaded directly from Sage Bionetworks.
“These data were generated as part of routine patient care and without AACR Project GENIE they would likely never have been shared with the global cancer research community,” said Dr. Charles L. Sawyers, AACR Project GENIE Steering Committee chairperson, chairperson of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center in New York and a Howard Hughes Medical Institute investigator. “We are committed to sharing not only the real-world data within the AACR Project GENIE registry but also our best practices, from tips about assembling an international consortium to the best variant analysis pipeline, because only by working together will information flow freely and patients benefit rapidly.”
The newly released data are fully de-identified in compliance with the Health Insurance Portability and Accountability Act. They are derived from patients whose tumors were genetically sequenced as part of their care at one of the eight international institutions that participated in the first phase of AACR Project GENIE. Therefore, the genomic data are clinical grade.
By releasing the data to the global cancer research community, the consortium aims to catalyze new clinical research that will accelerate the pace of progress against cancer. There are many ways in which the data can be exploited to benefit patients in the future, including through the following: the validation of gene signatures of drug response or prognosis, the ability to identify new patient populations for drugs previously approved by the U.S. Food and Drug Administration, the expansion of patient populations that will benefit from existing drugs and the identification of new drug targets and biomarkers.
The eight institutions participating in AACR Project GENIE phase 1 are the Dana-Farber Cancer Institute in Boston, Gustave Roussy Cancer Campus in Paris, The Netherlands Cancer Institute in Amsterdam, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Md., Memorial Sloan Kettering Cancer Center in New York, Princess Margaret Cancer Centre in Toronto, Ontario, the University of Texas MD Anderson Cancer Center in Houston, Texas, and Vanderbilt-Ingram Cancer Center in Nashville, Tenn.
To expand the AACR Project GENIE registry, the consortium is already accepting applications for new participating centers starting today, which is a year sooner than originally anticipated.
Where to do oncology clinical research
Good science can happen anywhere, but some places might give a bit of an edge potentially, according to KMR Group’s recently completed “Best Places For Clinical Research” report series for 2016. The Best Places series continues to highlight the strengths and weaknesses of nearly 100 countries for over a dozen different therapy areas and diseases. This year’s analyses are said to “confirm existing industry trends while highlighting some surprising new shifts.”
The Best Places For Clinical Research reports ranks countries for specific disease areas using eight key performance indicators that assess performance, infrastructure, patient access and cost. The results are presented for each individual metric in addition to an aggregate score which combines all of them together to come up with a singular overall rank.
This year, the oncology-focused report highlights the strength of Eastern Europe, which now ranks second regionally right below Asia (excluding Japan). North America and Western Europe rank third and fourth respectively, while the Middle East and Africa perform the worst with the lowest regional scores.
China remains the top country overall, but Russia, Ukraine, Poland and Romania rank close behind. All these countries have relatively strong infrastructures for oncology, KMR notes, but “really outperformed other countries with their strong recruitment rates and access to patients. This highlights the importance emerging markets have had for the industry over the last several years in maintaining and improving clinical development performance.”
As for the United States, which now ranks seventh globally, it has the strongest infrastructure and patient volume across countries, but has high costs and only average recruitment performance, which hindered its ranking.
“Understanding the shortcomings of certain countries within diseases as well as identifying the strongest performers is critical in trial planning and management. These reports serve as a strong foundation that can play a critical role in the early stage planning process and set reliable benchmarks in trial plans,” comments Linda Martin, president and founder of KMR Group.
Aduro presents preclinical data supporting clinical development of anti-APRIL antibody
BERKELEY, Calif. & OSS, The Netherlands—Near the end of 2016, Aduro Biotech Inc., a biopharmaceutical company with three distinct immunotherapy technologies, announced the presentation of data from preclinical studies supporting the clinical development of the company’s proprietary monoclonal antibody (mAb) BION-1301, a humanized anti-APRIL (A PRoliferation-Inducing Ligand) antibody for the treatment of multiple myeloma.
Data from these in-vivo and in-vitro preclinical studies are said to demonstrate that BION-1301 effectively neutralized APRIL, preventing its binding to BCMA (B cell maturation antigen), an essential receptor expressed on multiple myeloma cells. Based on the mechanism of action and antitumor activity observed in earlier preclinical studies with the parental anti-APRIL antibody, hAPRIL.01A, BION-1301 has the potential to inhibit multiple myeloma tumor growth, survival and chemoresistance.
These data were highlighted in a poster presentation at the 58th American Society of Hematology Annual Meeting and Exposition.
“In patients with multiple myeloma, there is an overabundance of APRIL, a ligand which plays a critical role in the proliferation of multiple myeloma cells,” stated Dr. Andrea van Elsas, chief scientific officer of Aduro Biotech Europe. “With BION-1301, which was derived from Aduro’s proprietary B-select antibody platform, we are blocking APRIL from binding to its target receptor, thereby inhibiting the growth and survival of multiple myeloma cells.”
“Based on the data to be presented later today, we believe BION-1301 represents a novel antibody with a novel mechanism of action that has potential in the treatment of multiple myeloma, alone or in combination regimens,” added van Elsas. “We look forward to advancing BION-1301 into clinical development in the coming year in our effort to bring much needed new treatment options to patients with multiple myeloma.”
In April 2016, Aduro announced the publication of a study entitled, “APRIL and BCMA promote human multiple myeloma growth, chemoresistance, and immunosuppression in the bone marrow microenvironment,” by Dr. Kenneth Anderson and Dr.Tai Yu-Tzu, Ph.D. of the Dana-Farber Cancer Institute. The article appeared in the June 2016 issue of the peer-reviewed journal Blood. The publication elucidates the roles of BCMA and its ligand APRIL in multiple myeloma, highlighting the potential therapeutic use of an agent that targets APRIL and fully blocks its interaction with its receptors. The research indicated that the parental antibody to BION-1301 halts tumor growth and overcomes drug resistance to chemotherapeutic agents lenalidomide and bortezomib in preclinical models.
Aduro is an immunotherapy company focused on the discovery, development and commercialization of therapies that transform the treatment of challenging diseases, and its technology platforms, which are designed to harness the body’s natural immune system, are being investigated in cancer indications and have the potential to expand into autoimmune and infectious diseases. Aduro’s LADD technology platform is based on proprietary attenuated strains of Listeria that have been engineered to express tumor-associated antigens to induce specific and targeted immune responses. This platform is being developed as a treatment for multiple indications, including pancreatic, ovarian, lung and prostate cancers, mesothelioma and glioblastoma. Additionally, a personalized form of LADD, or pLADD, is being developed utilizing tumor neoantigens that are specific to an individual patient’s tumor.
Scripps scientists uncover new way to defeat therapy-resistant prostate cancer
JUPITER, Fla.—A recent study led by scientists from the Florida campus of The Scripps Research Institute (TSRI) reportedly sheds light on a signaling circuit in cells that drives therapy resistance in prostate cancer. The researchers found that targeting the components of this circuit suppresses advanced prostate cancer development. The study, led by Jun-Li Luo, a TSRI associate professor, was published in Molecular Cell.
Currently, the most effective treatment for advanced prostate cancer is to deprive the cancer of what feeds it—androgen hormones such as testosterone. Unfortunately, almost all patients eventually develop resistance to this therapy, leaving doctors with no options to counteract the inevitable.
The new study shows that a “constitutively active” signaling circuit can trigger cells to grow into tumors and drive therapy resistance in advanced prostate cancer. A cell signal pathway with constitutive activity requires no binding partner (ligand) to activate; instead, the signaling circuit continually activates itself.
This signaling circuit, which is composed of the protein complex IκBα/NF-κB (p65) and several other molecules, controls the expression of stem cell transcription factors (proteins that guide the conversion of genetic information from DNA to RNA) that fuel the aggressive growth of these resistant cancer cells.
“The fact that the constitutive activation of NF-kB in the circuit is independent of traditional activation opens the door for potential treatment options,” said Luo.
NF-kB plays important roles in cancer development, and it is regarded as a very important targets for cancer therapy. However, the use of NF-kB inhibitors in treating cancer is complicated by severe side effects related to immunosuppression caused by indiscriminate inhibition of NF-kB in normal immune cells.
Luo noted that targeting the other non-IκBα/NF-κB components in this signaling circuit would avoid the suppression of NF-κB in normal immune cells while keeping the potent anticancer efficacy.
In addition to IκBα/NF-κB, the signaling circuit includes the microRNA miR-196b-3p, Meis2 and PPP3CC. While miR-196b-3p promotes tumor development, Meis2, which is an essential developmental gene in mammals, can disrupt the circuit when overexpressed. The protein PPP3CC can inhibit NF-κB activity in prostate cancer cells.
“Disrupting this circuit by targeting any of its individual components blocks the expression of these transcription factors and significantly impairs therapy-resistant prostate cancer,” said Ji-Hak Jeong, the first author of the study and a TSRI research associate.
Dolomite system could accelerate cancer research
LONDON—As reported by Dolomite Bio, researchers at the Institute of Cancer Research (ICR) in the United Kingdom are taking advantage of the single-cell encapsulation capabilities of Dolomite Bio’s Single Cell RNA-Seq System to investigate resistance mechanisms in prostate cancer.
“Our team is focused on studying treatment resistance in prostate cancer patients, looking at the biochemical mechanisms responsible,” explained Karolina Nowakowska, a Ph.D. student at ICR. “My project is based on using single-cell sequencing to help identify the specific genes which lead to treatment resistance, trying to identify biomarkers and, in the longer term, treatments which will allow a more personalized approach to therapy.
“Initially, I was using FACS to perform manual sorting of cells into individual wells, but this is both time consuming and laborious, limiting me to a maximum of 20 cells per experiment. As throughput is crucial in biomarker discovery, we wanted to perform our investigations on a much larger scale and, following the publication by Macosko [and colleagues, in the Cell paper “Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets”], we decided that microfluidics was the way forward.”
After a demonstration of the system at Dolomite Bio’s headquarters near Cambridge, the ICR team chose the Single Cell RNA-Seq System, and reportedly can now run more than 1,000 cells per experiment.
“Although we have only just finished optimizing our protocols, the throughput is very impressive and the system offers good reproducibility,” Nowakowska said. “The beauty of this technique is that it allows you to view many cellular events simultaneously and, once optimized, it’s more cost effective than manually sorting and sequencing cells.”
Fortress Biotech announces publication regarding MB‐101 for glioblastoma
NEW YORK— Biopharmaceutical company Fortress Biotech Inc. announced recently that a patient case study from the Phase 1 clinical trial of MB-101 (IL13Rα2-specific chimeric antigen receptor engineered T cells) for the treatment of glioblastoma (GBM) was published in the Dec. 29 edition of the New England Journal of Medicine. MB-101 is the lead development candidate of Mustang Bio Inc., a Fortress company.
The research, led by Dr. Stephen J. Forman, Dr. Christine Brown and Dr. Behnam Badie at City of Hope, describes a 50-year-old male patient with recurrent multifocal glioblastoma and spinal tumors who had failed standard-of-care tumor resection, radiation therapy and temozolomide. The patient received multiple infusions of MB-101, which was developed from his own genetically modified T cells, first into the resected tumor cavity as part of the Phase 1 study, and then, following tumor growth distal to the resected cavity, under a compassionate use protocol the patient received MB-101 infusions into the ventricular system. This novel approach had not been previously tested.
After treatment with intraventricular MB-101, regression of all intracranial and spinal tumors was observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid. During intraventricular treatment, systemic dexamethasone was gradually eliminated, and the patient returned to normal life and work activities. The clinical response continued for 7.5 months after the initiation of MB-101. Infusions of MB-101 were well tolerated and not associated with any toxic effects of grade three or higher.
“We are excited to share this unprecedented research conducted by Mustang’s partners at City of Hope, which confirms the potential of MB-101 to be a breakthrough immunotherapeutic targeted against GBM, an almost universally fatal brain tumor,” said Dr. Lindsay A. Rosenwald, Fortress Biotech’s chairman, president and CEO.
“As the first patient ever to receive intraventricular delivery of CAR T cells for brain tumors, we see this as proof of concept that CAR T cells can be delivered safely and with remarkable effect to patients with GBM,” said Michael S. Weiss, Mustang Bio’s executive chairman. “This robust response has prompted the expansion of our Phase 1 study to evaluate intraventricular administration in a larger cohort of patients. Given the poor outcomes for patients with GBM, we believe if we see additional patients with this type of response that we can explore a possible accelerated approval pathway, similar to that proposed by some of the other CAR T companies, which are targeting different forms of cancer.”
City of Hope is evaluating MB-101 in an ongoing Phase 1 study in patients with recurrent and refractory malignant GBM. GBM is the most common brain and central nervous system malignancy, accounting for 15.1 percent of all primary brain tumors and 55.1 percent of all gliomas. Chemotherapy with temozolomide and radiation are shown to extend median survival from approximately 12 to 15 months, while surgery remains the standard of care. GBM remains difficult to treat due to the inherent resistance of the tumor to conventional therapies. Treatment is further complicated by the susceptibility of the brain to damage, the difficulty of the brain in repairing itself and the limitations of drugs in crossing the blood-brain barrier. Immunotherapy approaches targeting brain tumors offer promise over conventional treatments.