Eureka! Have we found it?
Research institutes use their prowess to help unlock discoveries for cancer treatment targets and pathways
So, even as we honor the upcoming American Association for Cancer Research annual meeting (a preview of which appears in this issue) by running this special section on oncology, let us also honor the spirit of discovery with some recent news from various research institutions that have put their academic and scientific muscle behind driving discovery-level work in the area of oncology therapeutics.
A step toward stopping metastasis
Scientists at the La Jolla, Calif., campus of The Scripps Research Institute (TSRI) released news of recent research they have conducted that could offer a leg up for efforts to target tumors before they metastasize.
The study, published recently in the Nature research journal Oncogene under the title “LTBP3 promotes early metastatic events during cancer cell dissemination,” shows that a protein called Latent TGFβ Binding Protein 3 (LTBP3) is the driver behind a “chain reaction” that leads some early developing tumors to grow new blood vessels—vessels which then become the pathways for spreading cancer cells throughout the body and setting the stage for metastasis early on.
“Lower LTBP3 levels appear to be associated with better prognosis in patients with certain types of cancer,” says Dr. Elena Deryugina, an assistant professor at TSRI and first author of the new study. Deryugina led the collaborative study with senior authors Dr. James P. Quigley, a TSRI professor, and Dr. Daniel Rifkin, a professor at the New York University School of Medicine.
According to TSRI, their research addresses a long-standing challenge in medicine, explaining that over the years, a potent growth factor molecule called TGFβ has become an area of high interest for many researchers in the oncology field. The reason? In a good cop/bad cop manner, TGFβ plays multiple roles in health and disease—specifically, it can be both a promoter and suppresser of tumor cell growth.
The problem, though, is that while TGFβ seems a promising cancer therapy target, researchers haven’t been able to figure out how to dampen its harmful effects without interfering with its normal roles in the body.
TSRI notes that, as long-time collaborators, Deryugina and Quigley have led research that shows that the initial steps of tumor metastasis can occur when a primary tumor is barely detectable. This work sparked their interest in the role of LTBP3 because they knew that LTBP3 partners with TGFβ to regulate its secretion, activation and maturation, but wondered what else LTBP3 might control. For example, could LTBP3 set TGFβ on its harmful path of action in early-stage tumors, and might LTBP3 have its own role, independent of TGFβ, in cancer metastasis?
The TSRI-led research used chick embryo tumor models and a rodent model of head and neck cancer to discover how LTBP3 is involved in the spread of aggressive tumor cells. They knocked down LTBP3 expression and secretion in human tumor cell lines representing carcinoma, head and neck carcinoma and a fibrosarcoma. In each model, the team found that without LTBP3, primary tumor cells could not metastasize efficiently.
“Our experimental findings showed that LTBP3 is active in the very early steps of metastatic spread,” said Quigley.
“Specifically, LTBP3 appears to help tumors grow new blood vessels in a process called angiogenesis, which is critical for tumor cell intravasation. That is when cancer cells enter into blood vessels of defined size and permeability,” added Deryugina.
Importantly, the new data is in line with clinical findings that LTBP3 levels can indicate better overall survival in cancer patients with early-stage head and neck carcinomas. Taken together, these findings suggest LTBP3 may be a good “upstream” drug target to treat early-stage tumors without affecting more complex roles of TGFβ in other parts of the body.
Next steps include investigating precisely how LTBP3 and TGFβ biochemically partner in the induction of new blood vessels deep within a tumor.
Curbing cancer growth by blocking nutrient access
About a month earlier, also from La Jolla, came news from the Salk Institute for Biological Studies of the publication of the paper “Pharmacological activation of REV-ERBs is lethal in cancer and oncogene induced senescence” in Nature that detailed a method—tested on glioblastoma brain tumors in mice—to curb the growth of cancer cells by blocking the cells’ access to certain nutrients. The approach takes advantage of knowledge on how healthy cells use a 24-hour cycle to regulate the production of nutrients.
“When we block access to these resources, cancer cells starve to death but normal cells are already used to this constraint, so they’re not affected,” said Dr. Satchidananda Panda, a professor in the Salk Institute’s Regulatory Biology Laboratory and lead author of the paper.
The circadian cycle, the intrinsic clock that exists in all living things, is known to help control when individual cells produce and use nutrients, among many other functions. As Salk notes, scientists previously discovered that proteins known as REV-ERBα and REV-ERBβ are responsible for turning on and off cells’ ability to synthesize fats, as well as their ability to recycle materials—a process called autophagy—throughout the day.
In healthy cells, fat synthesis and autophagy are allowed to occur for about 12 hours a day when REV-ERB protein levels remain low. The rest of the time, higher levels of the REV-ERB proteins block the processes so that the cells are not flooded with excessive fat synthesis and recycled nutrients.
Given this dynamic, it is unsurprising that past researchers have explored compounds to activate REV-ERBs in an effort to treat various metabolic disorders by halting fat synthesis. But taking a wholly different path, Panda and his colleagues decided to examine whether activating REV-ERBs would slow cancer growth, since cancer cells rely heavily on the products of both fat synthesis and autophagy to grow.
“While current cancer research was investigating established cancer hallmarks/characteristics, we decided to explore something completely new,” said Gabriele Sulli, a Salk research associate and the paper’s first and co-corresponding author. “Given the importance of the circadian clock in the regulation of many cellular and physiological processes, we hypothesize that targeting the circadian clock with drugs may open the way to novel anticancer strategies. This study is very exciting because it sheds light on a new uncharacterized way to treat cancer with very limited toxicity.”
“We’ve always thought about ways to stop cancer cells from dividing,” added Panda. “But once they divide, they also have to grow before they can divide again, and to grow they need all these raw materials that are normally in short supply. So cancer cells devise strategies to escape the daily constraints of the circadian clock.”
Although cancer cells contain REV-ERB proteins, somehow they remain inactive. Panda’s team used two REV-ERB activators that had already been developed—SR9009 and SR9011—in studies on a variety of cancer cells, including those from T cell leukemia, breast cancer, colorectal cancer, melanoma and glioblastoma. In each cell line, treatment with the REV-ERB activators was enough to kill the cells. The same treatment on healthy cells had no effect. “Activating REV-ERBs seemed to work in all the types of cancer we tried,” explained Panda. “That makes sense because irrespective of where or how a cancer started, all cancer cells need more nutrients and more recycled materials to build new cells.”
The researchers then tested the drugs on a new mouse model of glioblastoma recently developed by Inder Verma, a professor in the Salk Institute’s Laboratory of Genetics. Once again, the REV-ERB activators were successful at killing cancer cells and stopping tumor growth but seemed not to affect the rest of the mice’s cells. Verma says the findings are exciting not only because they point toward existing REV-ERB activators as potential cancer drugs, but also because they help shine light on the importance of the link between the circadian cycle, metabolism and cancer.
“These are all fundamental elements required by all living cells,” says Verma. “By affecting REV-ERBs, you get to the heart of how cells grow and proliferate, but there are lots of other ways to get at this as well.”
Verma says his group is planning follow-up studies on how, exactly, the REV-ERB activators alter metabolism, as well as whether they may affect the metabolism of bacteria in the microbiome, the collection of microbes that live in the gut. Panda’s team is hoping to study the role of other circadian cycle genes and proteins in cancer.
A master switch for cancer immunotherapy?
Heading backward yet another month, and heading back to TSRI—though this time the Jupiter, Fla., campus of the institute—research highlighted in Nature in the paper “Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumors” points to the discovery of a possible master switch for programming cancer immunotherapy.
As TSRI notes, during infection or tumor growth, a type of specialized white blood cells called CD8+ T cells rapidly multiply within the spleen and lymph nodes and acquire the ability to kill diseased cells, and some of these killer T cells then migrate to where they are needed to fight the invaders, whether they are microbes or tumor cells. The question, though, has been, “How do killer T cells learn to leave their home base and amass within specific tissues like the skin, gut and lung or solid tumors?”
And the answer to this question is critical for many oncology researchers who need to know what factors lead to T cells functioning beyond the lymphoid system so that they can better develop cancer-fighting immunotherapy strategies. What researchers from The Scripps Research Institute—along with colleagues at the University of California, San Diego—reported in their recent paper was the discovery that a protein called Runx3 programs killer T cells to establish residence in tumors and infection sites.
“Runx3 works on chromosomes inside killer T cells to program genes in way that enables the T cells to accumulate in a solid tumor,” said Dr. Matthew Pipkin, an associate professor in the Department of Immunology and Microbiology on the Florida campus of The Scripps Research Institute.
There are two main strategies in cancer immunotherapy that employ killer T cells, Pipkin said. Checkpoint inhibitor blockade unleashes killer T cells, prompting them to accumulate in tumors more aggressively. Adoptive cell transfer, meanwhile, involves reinfusing a patient’s own immune cells after they have been engineered in the lab to recognize and destroy the patient’s specific cancer.
The adoptive cell transfer strategy has worked stunningly well in some blood cancers associated with the lymphoid system, so far, but there appears to be less efficient activity of T cells in solid tumors, Pipkin said, adding: “The gene programs and signals for how the T cells take up residence in tissues outside of the general circulation was not really well understood.”
To discover factors that control T cell residency beyond the lymphoid system, Pipkin’s team worked collaboratively with the laboratory of UC San Diego’s Ananda Goldrath, who compared the gene expression of CD8+ T cells found in non-lymphoid tissue to those found in the general circulation. From a list of potential factors, they employed an RNA interference screening strategy which can test the actual function of thousands of factors simultaneously. Pipkin’s lab had developed the screening strategy in collaboration with Shane Crotty at the La Jolla Institute for Allergy and Immunology.
“We found a distinct pattern,” Pipkin said. “The screens showed that Runx3 is one at the top of a list of regulators essential for T cells to reside in nonlymphoid tissues.” Moreover, Runx3 was able to engage a specific gene program that is found in natural tissue-resident and tumor infiltrating CD8+ T cells, he said.
The group further assessed whether Runx3 had a role in directing white blood cells that attack solid tumors in mouse melanoma models. They found that adoptive cell transfer of cancer-specific killer T cells that overexpressed Runx3 delayed tumor growth and prolonged survival, while mouse models treated with those lacking Runx3 fared much worse than normal.
“If we enhance Runx3 activity in the cells, the tumors are significantly smaller and there is greater survival compared to the control group,” Pipkin said.
Knowing that modulating Runx3 activity in T cells influences their ability to reside in solid tumors opens new opportunities for improving cancer immunotherapy, Pipkin said, noting: “The upshot is we could probably use Runx3 to reprogram adoptively transferred cells to help drive them to amass in solid tumors.”
Cell lines to accelerate cancer therapies
Concluding with something research- and discovery-oriented but not in the realm of published studies, we have news from late last year that the Philadelphia-based Gene Editing Institute of Christiana Care’s Helen F. Graham Cancer Center & Research Institute signed an agreement to provide genetically modified cell lines to Analytical Biological Services Inc. (ABS) of Wilmington, Del., to help speed up the development of next-generation cancer therapies.
Under a three-year agreement, the Gene Editing Institute will act as sole provider of gene-editing services and genetically modified cell lines to ABS for replication, marketing and distribution to leading pharmaceutical and biomedical research companies worldwide.
“This agreement with ABS will speed the progress in the discovery of effective cancer therapies and accelerate the path to prevention, diagnosis and treatment of many forms of cancer,” said Dr. Nicholas J. Petrelli, the Bank of America endowed medical director of the Helen F. Graham Cancer Center & Research Institute.
“This partnership greatly enhances our capability to provide the highest-quality genetically engineered cells for drug discovery,” Dr. Charles Saller, ABS president and CEO, commented in a press release. “Our partners at the Gene Editing Institute are advancing molecular medicine, and their expertise adds a new dimension to our efforts to speed up drug discovery.”
“One goal of The Gene Editing Institute is to develop community partnerships that can advance translational cancer research,” added Dr. Eric Kmiec, founder and director of the Gene Editing Institute. “The Gene Editing Institute is driving innovation in gene engineering, and ABS has the know-how to grow and expand the cells in sufficient quantities, as well as to market them to pharmaceutical and biotechnology clients for drug screening and research.”
The Gene Editing Institute is one of the leaders in designing the tools that scientists need to manipulate and alter human genetic material more easily and more efficiently. Last year, scientists at the Gene Editing Institute described in the journal Scientific Reports how they combined CRISPR and short strands of synthetic DNA to greatly enhance the precision and reliability of the CRISPR gene editing technique. Called Excision and Corrective Therapy, or EXACT, this new tool acts as both a Band-Aid and a template during gene mutation repairs.
By inactivating a single gene, scientists can test if it affects tumor formation or somehow alters the response to cancer therapies. Similarly, inserting a gene into a cell can produce a gene product that is a target for potential new drugs.
“Gene editing and the CRISPR technology is having a major impact on anticancer drug development because it allows us to validate the target of the candidate drug,” Kmiec remarked. “Pharmaceutical companies want to use gene-editing tools to identify new targets for anticancer drugs and to validate the targets they already have identified.”
Tumors on trial
A roundup of recent clinical trial updates in the oncology realm
CAMBRIDGE, Mass. & BEIJING, China—BeiGene Ltd., a commercial-stage biopharmaceutical company focused on developing and commercializing molecularly targeted and immuno-oncology drugs for the treatment of cancer, presented preliminary clinical data from patients with urothelial carcinoma (UC) enrolled in an ongoing Phase 1 clinical trial of tislelizumab, an investigational anti-PD-1 antibody, at the 2018 Genitourinary Cancers Symposium in San Francisco in February. The preliminary Phase 1 data suggest that tislelizumab was generally well tolerated and exhibited objective responses in patients with UC.
“Tislelizumab is currently being evaluated in five pivotal trials globally and in China, including a pivotal trial in patients with previously treated, PD-L1-positive, locally advanced or metastatic urothelial carcinoma in China. This is the first presentation of tislelizumab data in the population with urothelial cancer, an area of unmet need. We are pleased by these preliminary results, which we believe provide an important foundation for our clinical understanding of tislelizumab’s efficacy and safety in specific patient populations both as a single agent and in combination,” commented Dr. Amy Peterson, chief medical officer for immuno-oncology at BeiGene.
Tyme tackles prostate cancer
SAN FRANCISCO—Tyme Technologies Inc., a clinical-stage biotech that was also presenting at the 2018 Genitourinary Cancers Symposium, announced efficacy and safety data from an ongoing Phase 2 trial of SM-88 in patients with non-metastatic, biochemical-recurrent prostate cancer (nmPC).
“Prostate cancer patients have limited treatment options and are likely to receive ADT (androgen deprivation therapy), a hormone therapy that lacks sufficient evidence of efficacy in non-metastatic prostate cancer and may produce considerable toxicities and a reduction in quality of life,” said Dr. Mack Roach III, a professor of radiation oncology and urology at the University of California, San Francisco. “Toxicities typically associated with ADT have not been seen with SM-88, which suggest that ADT may be avoided or delayed without progression in patients with non-metastatic prostate cancer. I look forward to continuing to work with Tyme to explore the benefits of SM-88 as an alternative to hormone therapy in prostate cancer patients, particularly those pursuing active surveillance.”
Currently, 92 percent of patients (12/13) have maintained radiographic progression-free survival (rPFS) with a median of 12 months since documented biochemical recurrence, and 10 months since starting SM-88 treatment. All 12 patients who have maintained rPFS also exhibited meaningful reductions in circulating tumor cells (CTCs), while the one patient experiencing radiographic progression had a rise in CTCs.
Array against melanoma
BOULDER, Colo. & CASTRES, France—Array BioPharma Inc. and Pierre Fabre in February announced results of the planned analysis of overall survival (OS) from the pivotal Phase 3 COLUMBUS trial in patients with BRAF-mutant melanoma. Treatment with the combination of encorafenib 450 mg daily and binimetinib 45 mg twice daily (COMBO450) reduced the risk of death compared to treatment with vemurafenib 960 mg twice daily. Median OS was 33.6 months for patients treated with COMBO450, compared to 16.9 months for patients treated with vemurafenib as a monotherapy.
“Many patients with BRAF-mutant melanoma still face significant challenges managing their disease, and there remains a substantial need for well-tolerated treatments that delay disease progression and improve overall survival,” said Dr. Keith T. Flaherty, director of the Termeer Center for Targeted Therapy at Massachusetts General Hospital Cancer Center and professor of medicine at Harvard Medical School. “This data suggests that the combination of encorafenib and binimetinib may have the potential to become a meaningful new therapy for patients with advanced BRAF-mutant melanoma.”
Genentech confronts kidney cancer
SOUTH SAN FRANCISCO, Calif.—Genentech, a member of the Roche Group, recently announced results from the positive Phase 3 IMmotion151 study of Tecentriq (atezolizumab) and Avastin (bevacizumab) as a first-line treatment for advanced or metastatic renal cell carcinoma. The study met its co-primary endpoint of investigator-assessed progression-free survival (PFS) in people whose disease expressed the PD-L1 (programmed death-ligand 1) protein. Those who received Tecentriq plus Avastin had a 26-percent reduced risk of disease worsening or death compared to people treated with sunitinib (median PFS: 11.2 vs. 7.7 months).
Initial observations from the co-primary endpoint of OS in the overall study population (intention-to-treat) were encouraging, but are still immature. Safety for the Tecentriq and Avastin combination appeared consistent with the known safety profile of the individual medicines and what was previously reported in the Phase 2 IMmotion150 study.
“This is the second positive Phase 3 study that includes Tecentriq and Avastin as part of a treatment regimen, providing further evidence to support the potential of this unique combination,” said Dr. Sandra Horning, chief medical officer and head of global product development.
Two trials provide lymphoma hope
HEIDELBERG, Germany—Feb. 1 saw Affimed N.V., a clinical-stage biopharmaceutical company focused on highly targeted cancer immunotherapies, report additional preliminary patient data from two separate clinical studies of its lead NK cell engager candidate AFM13. The data demonstrate that AFM13 was well tolerated and showed promising therapeutic efficacy both in combination with the anti-PD-1 antibody Keytruda (pembrolizumab) in Hodgkin lymphoma and as a monotherapy in CD30-positive lymphoma.
“We are extremely encouraged by these new data, which indicate that the first-in-class NK cell engager AFM13 has achieved clinically meaningful responses both as single agent and in combination with a checkpoint inhibitor,” said Dr. Adi Hoess, CEO of Affimed. “In particular, in our combination trial with Keytruda, we are excited to have increased both overall and complete metabolic response rates.”
Eisai enters into licensing deal with Adlai Nortye
TOKYO—January saw Eisai Co. Ltd. announce that it had entered into a licensing agreement granting exclusive rights concerning the research, development, manufacture and marketing of Eisai’s in-house discovered potential anticancer agent E7046, which is an investigational prostaglandin E2 (PGE2) type EP4 receptor antagonist, to Adlai Nortye Biopharma Co. Ltd. in all regions outside of Japan and part of Asia (excluding China).
E7046 is an orally administered, selective EP4 receptor antagonist discovered by Eisai’s U.S. Andover research facility. It is suggested that PGE2 signals through EP4 receptors may suppress the antitumor activity of immune cells. By inhibiting EP4, E7046 is expected to act on the tumor microenvironment via a different mechanism to immune checkpoint inhibitors to potentially demonstrate antitumor effects.
Currently, E7046 is being investigated as a monotherapy in a Phase 1 clinical study as well as a Phase 1b clinical study in combination with radiotherapy/chemoradiotherapy.
Adlai Nortye is a science-led clinical-stage biopharmaceutical company dedicated to discovering, developing and commercializing new and effective immunotherapy for patients with cancer. Eisai positions oncology as a key therapeutic area, and is aiming to discover revolutionary new medicines with the potential to cure cancer. By licensing E7046 to Adlai Nortye, which is developing several tumor immunotherapies that have synergies with E7046, Eisai aims to maximize the value of the agent in order to hopefully contribute to the treatment of patients in the future who need tumor immunotherapies as soon as possible.
New MOA for Aptamer with therapeutic potential against NHL
IRVING, Texas—Caris Life Sciences was recently involved in a data presentation at the 59th American Society of Hematology Annual Meeting & Exposition in Atlanta, demonstrating the identification of a new mechanism of action to treat non-Hodgkin lymphoma (NHL). The company uses its proprietary ADAPT Biotargeting System to find novel molecules and mechanisms for therapeutic and diagnostic applications.
The study, entitled “Aptamer C10.36 Reveals a Ribonucleoprotein Complex on the Surface of Non-Hodgkin Lymphoma Cells Providing Candidates for Multi-Target Therapeutics,” showed that the single-stranded DNA aptamer C10.36 specifically binds to heterogeneous nuclear ribonucleoprotein U (hnRNP U), a protein that controls pre-mRNA splicing, which is a highly dynamic process enabling cells to rapidly adjust to changing conditions by creating a range of mRNA variants that encode different proteins.
Cancer cells frequently display splicing regulatory factors, such as heterogeneous nuclear ribonucleoproteins on their surface, and show broad dysregulated pre-mRNA splicing. If the splicing machinery is disrupted, it is believed “splicing chaos” may occur leading to cell death.
Results of this study showed that C10.36 binding to cell-surface hnRNP U resulted in internalization of the complex, disruption of pre-mRNA splicing and cell death in a subset of NHL cell lines in vitro. The authors concluded that the aptamer, C10.36, binds to hnRNP U and kills NHL cells via a novel mechanism of interfering with pre-mRNA splicing.
“This paper further validates the capabilities of our aptamers to not only identify biomarkers for use in diagnostics and drug development, but to also identify new pathways and therapeutic candidates that impact them. Using the Adapt Biotargeting System, we can create and identify thousands to millions of synthetic molecules and targets simultaneously,” said Dr. David Spetzler, president and chief scientific officer of Caris. “Our next steps are to continue to characterize the breadth of activity of C10.36 across various cancer cell lineages and to prepare for further validation in vivo.”
Vedanta expands network supporting microbiome therapeutics for cancer immunotherapy
CAMBRIDGE, Mass.—Vedanta Biosciences late last year announced new translational medicine collaborations in cancer immunotherapy with Leiden University Medical Center and the University of South Alabama Mitchell Cancer Institute, and it also announced the expansion of its translational medicine collaboration in cancer immunotherapy with NYU Langone Health and its Perlmutter Cancer Center.
Researchers at these institutions have been collaborating with Vedanta Biosciences to analyze microbiome clinical data from interventional checkpoint inhibitor studies to identify microbiome signatures associated with response to immunotherapy and key mechanisms through which the gut microbiota modulate immunotherapeutic responses.
“Data from our ongoing clinical collaborations in melanoma show that gut bacteria signatures could help determine if a cancer immunotherapy will work,” said Dr. Bruce Roberts, chief scientific officer of Vedanta Biosciences. “We’re pleased to expand our research collaborations into other forms of cancer, with the ultimate goal of identifying ways to change the microbiome to increase the proportion of patients and types of cancer patients who respond to immunotherapies.”
Vedanta Biosciences’ immuno-oncology programs include lead product candidate VE800, which has been shown in preclinical models to activate CD8+ T cells, improve CD8+ T cell tumor infiltration and improve survival in several cancer models in combination with checkpoint inhibitors. Vedanta anticipates filing an Investigational New Drug application for this candidate in 2018.
Speeding up timelines for CAR-T trials
SHANGHAI & CUPERTINO, Calif.—Cellular Biomedicine Group Inc. (CBMG), a clinical-stage biopharmaceutical firm engaged in the development of immunotherapies for cancer, recently announced its plan to configure part of its facility in Shanghai with GE Healthcare’s FlexFactory platform, which will be designed to speed up manufacturing timelines for its cell therapy clinical trials and commercial launch.
“This is a productivity revolution in the CAR-T space—this new generation of semi-automated and standardized CAR-T manufacturing capabilities created by GE Healthcare and CBMG may allow cell therapy to provide an optimal platform and opportunity for general oncology patients. This long-term collaboration with GE could help us utilize digital technology, semi-automation and analytics, in an effort to reduce overall costs and deliver treatments to patients more efficiently,” said Tony (Bizuo) Liu, CEO of CBMG.
GE Healthcare’s FlexFactory solution will support CBMG by providing process development and training services, cell processing equipment, semi-automation capabilities and digital connectivity solutions—all of which support current good manufacturing practices (cGMP)-compliant manufacturing. CBMG plans to use its FlexFactory to speed up its timelines for commercializing its CAR-T cell therapies, targeting various blood and solid tumor cancers.
“With the rate in which cell therapies are moving through clinical trials, we understand how critical it is for companies to scale out manufacturing process capabilities, while still meeting clinical development timelines and remaining cost effective. We are committed to collaborating with cell therapy manufacturers on their journey from trials to industrialization, as they look to ultimately deliver these groundbreaking therapies to thousands of patients around the world,” said Ger Brophy, general manager of cell therapy for GE Healthcare Life Sciences.