Pushing the tumor boundaries
Things are always busy in the field of cancer research, but perhaps they’re especially hectic right now, given that news of four interesting and very novel oncology-related items showed up in the DDNews email in a span of less than 36 hours, just as the June 2018 issue was nearing the layout stage.
We don’t doubt that other uncharted (or barely charted) waters exist in the sea of oncology R&D and are currently being reported on as well, but since this quartet arrived so conveniently clumped together and right on our electronic doorstep, let’s give them the spotlight for right now.
Two-pronged antibodies draw immune killers directly to cancer cells
JUPITER, Fla.—In the lab of biochemist and immunologist Dr. Christoph Rader, an associate professor at The Scripps Research Institute (TSRI), scientists have engineered a new type of anticancer antibody that is intended to enhance nature’s cancer-fighting strategies by attracting killer T cells directly to cancer cells covered with a distinctive protein.
Referred to as “T-cell engaging bi-specific antibodies,” these novel weapons in the fight against cancer are designed to attack malignant cells but leave healthy cells untouched—all thanks to their selective targeting system. That targeting system homes in on ROR1 specifically, a protein found on the surface of several types of cancer cells.
“Once the T cells are recruited and activated, they release cytotoxic molecules that penetrate the target cells and kill them,” Rader said. “Natural antibodies can’t do this. You have to engineer them in a bispecific fashion to do this.”
Granted, bispecific antibodies themselves aren’t a new area of research, but this particular antibody and potential therapeutic may be more versatile than most.
As Rader explained, ROR1 is an excellent target for a “smart” cancer-fighting system because it is seen only in mature cells that are malignant. Rader first discovered ROR1’s activity in leukemia a decade ago while working at the National Cancer Institute.
“ROR1 is expressed during embryogenesis, and then it is tightly down-regulated after birth. It later reappears in both blood cancers and solid malignancies,” Rader said, adding that it has been found on malignant cells, including lung, breast, ovarian and blood-based cancers. “One of the most unique aspects of this bi-specific antibody is that it can work in so many different cancer indications.”
Also on the more novel side of bispecific antibody R&D is the duration of activity for this particular antibody. Rader credits Dr. Junpeng Qi, first author of the study on their bispecific ROR1 work and a postdoctoral associate at TSRI, with engineering a group of bispecific antibodies that stay active in animal models for about five days—which he points out is a feat compared with current approaches. The one U.S.-approved bispecific antibody therapeutic for cancer right now—against B cell acute lymphoblastic leukemia—stays active for a couple of hours, Rader said.
“Junpeng used a component of natural antibodies for this bispecific antibody that gives it not only a larger size, but also the ability to be recycled and stay in the blood longer,” Rader explained. “They are not there eternally, though. You get rid of them eventually, which is important for avoiding systemic toxicity.”
The scientists’ work is described in the article “Potent and Selective Antitumor Activity of a T-Cell Engaging Bispecific Antibody Targeting a Membrane-Proximal Epitope of ROR1,” which appeared online May 29 in the journal Proceedings of the National Academy of Sciences.
Also worth noting is that Rader is particularly interested in applying his bispecific antibodies to HER2-negative breast cancer, a type of breast cancer with fewer treatment options than many other cancers. “If you look at ROR1 expression in breast cancer, you see that the patients who are HER2-negative are often ROR1-positive,” he noted. “These breast cancer patients might benefit.”
Block a protein, block the bladder cancer
DUARTE, Calif.—In what is said to be the first published report on an FGFR3 inhibitor in patients with advanced bladder cancer, we have news out of the kidney cancer research team at City of Hope about a novel drug called BGJ398. As noted in research led by Dr. Sumanta Kumar Pal, an associate clinical professor at City of Hope and the co-director of the Kidney Cancer Program there, BGJ398 blocks a key protein—FGFR3—that drives bladder cancer, successfully treating a specific population of patients with advanced bladder cancer.
The research was published in Cancer Discovery under the title “Efficacy of BGJ398, a fibroblast growth factor receptor 1–3 inhibitor, in patients with previously treated advanced urothelial carcinoma with FGFR3 alterations.”
Advanced bladder cancer is usually fatal, and the five-year survival rate for stage IV bladder cancer is only about 15 percent. However, in a hopeful sign, the City of Hope investigators saw substantial tumor shrinkage and delays in tumor growth with abnormalities in the FGFR3 protein in patients who were treated with BGJ398. Among 67 patients treated, an overall response rate of 25.4 percent was observed, and an additional 38.8 percent of patients had disease stabilization, translating to a disease control rate of 64.2 percent.
According to Pal, “The activity suggests a new possible paradigm for treatment—specifically, screening for relevant mutations in bladder cancer and treating accordingly. With further investigation, agents like BGJ398 could fit a huge unmet need in this disease.”
And, as noted by the authors in the paper, “Although the treatment landscape of metastatic urothelial carcinoma is evolving, there is still a need for novel therapies in this domain. Following platinum-based chemotherapy, cytotoxic therapy has been associated with limited responses. While there is much excitement surrounding immunotherapy, a Phase 3 trial demonstrating superiority over checkpoint blockade inhibitor therapy over chemotherapy reported a response rate of just 21 percent. Current preliminary data suggest that tumors that harbor FGFR3 alterations are more likely to be resistant to immune checkpoint blockade, indicating a role for molecularly targeted therapies.”
Antifungal drug eliminates sleeping bowel cancer cells
LONDON—From a novel therapeutic we move on to a novel use for a drug intended for something very non-oncological. Specifically, an antifungal medication commonly prescribed for toenail infections could help eliminate dormant cells within bowel tumors, according to new research funded by Cancer Research UK and published in the Journal of Experimental Medicine.
Researchers at the Cancer Research UK Cambridge Institute say they have shown in laboratory studies of mice that itraconazole effectively halts the growth and progression of certain types of bowel cancer. The next step will be to see if this holds true in patients with the disease.
Dr. Simon Buczacki, co-lead author and a Cancer Research UK clinician scientist, said: “One of the biggest challenges in treating any cancer is the diversity of different cells within the same tumor. We’ve targeted a type of cell that lies asleep within bowel tumors, remaining unresponsive to treatment and putting the patient at risk of their cancer coming back.”
The Cambridge team characterized the molecular nature of dormant bowel cancer cells, and they identified two key pathways involved in cell dormancy. In so doing, they found for the first time that itraconazole blocked signals from a pathway called Wnt, which is implicated in the growth and spread of many different cancers. This led to the tumors collapsing in the mice—dormant cells disappeared and the tumor stopped growing.
“What’s interesting is that this drug seems to kick both dormant and non-dormant cells into action,” added Buczacki. “It forces cells back into a short cycle of growth before slamming on an irreversible ‘stop’ button, entering a permanent standstill that’s known as senescence.”
The researchers hope to set up a clinical trial where they can test its effect on patients with advanced bowel cancer. They also intend to investigate whether this drug could be more effective in combination with other treatments like chemotherapy.
“This innovative study has taken a step toward addressing one of the biggest challenges in cancer research. Tumors are made up of many different types of cancer cells, which can evolve separately and respond to treatments differently,” said Prof. Greg Hannon, director of the Cancer Research UK Cambridge Institute. “The presence of drug-resistant, dormant tumor cells is a problem in many types of cancer. If we find ways to target these cells in bowel cancer, it might provide insights into tackling the problem of dormant tumor cells more broadly.”
RNA-modifying tool aimed at correcting genetic diseases, including a driver of TNBC
JUPITER, Fla.—And finally, after beginning with TSRI’s Florida campus with this roundup article, we finish there as well, with news of RNA editing to fight disease. As TSRI notes, much of the focus with gene-editing technologies has been on developing technologies such as CRISPR/Cas9. At TSRI, though, chemist Dr. Matthew D. Disney has taken a different approach, developing a small-molecule-based tool that acts on RNA to selectively delete certain gene products.
Disney’s deletion tool is said to open the possibility of creating drugs that can be taken conveniently as pills to correct genetic diseases by destroying toxic gene products and chemically controlling the body’s defense mechanisms. The paper, “Small molecule targeted recruitment of a nuclease to RNA,” was published online by the Journal of the American Chemical Society.
“These studies, like much science, were about a decade in the making. We are very excited to see how this initial application evolves,” Disney says. “This research further shows that RNA is indeed a viable target to make medicines.”
While about 2 percent of our genome encodes proteins, 70 to 80 percent of the genome is transcribed into RNA, potentially offering significantly more druggable targets, according to Disney. Until recently, however, most researchers considered RNAs undruggable, because of their small size and relative lack of stability.
Disney’s innovation tethers a drug-like molecule—one engineered to bind precisely and selectively to a specific RNA—to a common RNA-degrading enzyme. The small-molecule/enzyme complex is designed to latch onto the undesirable gene product and destroy it. Disney named the technology RIBOTAC, short for “ribonuclease-targeting chimeras.”
To test the RIBOTAC technology, Disney chose for his RNA-degrading enzyme RNase L, which is a critical part of the human antiviral immune response. Present in small amounts in every cell, production of RNase L typically surges on viral infection to destroy the viral RNA and overcome the illness.
For the other piece of the RIBOTAC complex, its drug-like molecule, Disney chose Targaprimir-96, a molecule engineered by his lab in 2016 to bind with a microRNA oncogene known to boost cancer cell proliferation, especially in difficult-to-treat triple-negative breast cancer: miRNA-96.
Destroying the oncogene led to a reawakening of the cancer cell’s innate self-destruct program via an increase in the FOXO1 gene, which ultimately spurred the death of the malignant cells, said Matthew G. Costales, first author of the paper and a graduate student in the Disney lab.
“Anchoring our previous work with Targaprimir-96 to the targeted recruitment of RNase L, we were able to program the RIBOTACs approach to only degrade cells that highly express the miRNA-96 oncogene, thus allowing FOXO1 to signal the selective destruction of triple-negative breast cancer cells,” noted Costales.
Awakening the body’s ability to kill its own cancer by exploiting cells’ RNA degradation system offers a novel approach to attacking cancer, according to Disney, who maintains that the RIBOTAC technology has potentially broad applications for cancer and other gene-driven diseases.
Guest commentary: The importance of cancer neoepitope discovery
By Dr. Renate Sekul, head of research and development, PEPperPRINT GmbH
Significant advances in cancer diagnosis and treatment have improved the outcomes in many types of cancer. Therapies targeting more selectively tumor-specific features such as tumor-associated antigens are part of the clinical routine. However, efficient treatments for advanced and highly aggressive neoplastic diseases are still missing.
Novel immune-modulatory approaches focus on the tumor microenvironment and try to activate the patient’s immune response to cancer tissue. A major breakthrough in cancer immunotherapy has been achieved with the introduction of checkpoint inhibitors. Checkpoint inhibition blocks signaling of the T cell surface receptors cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed death 1 (PD1), thereby increasing the T cell response towards tumor cells and ideally causing tumor regression. Checkpoint inhibitors are already approved for such cancers as metastasized melanoma or non-small cell lung cancer; clinical studies in other malignancies are ongoing. Regardless of these achievements, though, only a part of the affected patient population responds to checkpoint inhibition—thus, reliable predictive biomarkers for patient stratification are urgently needed.
Other immune treatments aim to target more specifically selected tumor-specific antigens and neoantigens. A variety of therapeutic cancer vaccines based on peptides, proteins or RNA show promising results in clinical trials. Adoptive T cell transfer uses tumor-infiltrating lymphocytes from tumor tissues, which are then stimulated and amplified with tumor antigens ex vivo and transferred back to patients to induce an effective antitumor response. Both approaches require the precise knowledge of tumor antigens and the underlying immunogenic epitopes.
Neoantigens are tumor-specific antigens that originate from somatic mutations in cancer cells. In recent years, high-throughput gene sequencing of normal and cancer tissues revealed tens of thousands of somatic mutations in major cancer types. Each tumor type exhibits an individual mutation profile, with shared and unique mutations between cancer patients. Because neoantigens are absent in healthy tissues, they are considered as ideal targets for novel immunotherapies.
Furthermore, the risk of autoimmune side effects will be significantly lower than addressing naïve tumor-associated antigens. Shared mutations can be addressed by more conventional approaches, such as treatment with monoclonal antibodies directed against such neoantigens, while unique mutations can form the basis for individualized therapies.
Tumor neoantigens can elicit strong immune responses with detectable antibody levels in patient sera. However, not every mutation can stimulate an immune reaction. Computer-assisted epitope prediction tools can help to select relevant MHC class I and class II neoepitopes for further validation in biological assays.
Whereas MHC class I prediction software such as NetMHC works reasonably well, the accurate prediction of MHC class II epitopes is still a challenge. The experimental analysis of antibody signatures in patient sera and the determination of the corresponding neoepitopes can be a very valuable alternative. High-resolution antibody profiling towards the complete set of neoepitopes will provide information on relevant MHC class II epitopes, even without knowing the patient’s HLA status. Analyzing the antibody fingerprint response against neoepitopes can be performed in a rapid fashion, even against large numbers of epitope peptides, and can help to precisely distinguish between immunogenic and non-immunogenic mutations.
Cancer neoepitope discovery on peptide arrays
Array-based technologies are ideally suited for analyzing antibody signatures. Thousands to tens of thousands of antigens can be screened simultaneously in a single experiment, requiring only minute amounts of patient sera. Bound antibodies are typically detected by a standard immunoassay using appropriately labeled detection antibodies.
High-density peptide microarrays are the method of choice for the epitope mapping of neoantigen proteins or peptides in a high-throughput mode. Personalized neoepitope libraries with thousands of peptides can be generated in a fast and economic fashion by on-chip synthesis technology, giving the complete neoepitope information within six weeks.
Combining high-throughput genomic sequencing technology with personalized peptide arrays for neoepitope discovery allows the straightforward discovery of immunogenic neoepitopes, patient by patient. Neoepitope targets can be identified within the shortest time frame, enabling the rapid translation of neoepitope information into high-precision cancer immunotherapies.
Immune responses to cancer neoepitopes will be a rich source of predictive biomarkers for patients, who will most likely benefit from current and future immunotherapies. Antibody responses to neoepitopes can guide immune modulatory therapies and indicate clinical responses to immune modulating therapies.
The described screening platform offers a high potential for the discovery of novel biomarkers for cancer diagnostic, disease monitoring and vaccine candidate selection.
Renate Sekul, Ph.D., received her doctorate in biochemistry in 1989 from the University of Cologne in Germany. Since then, she has worked in different pharmaceutical and biotech companies in the field of peptide and small-molecule drug discovery in various indication areas. She is an expert in preclinical drug discovery, and her research fields comprise peptide synthesis and characterization, protein biochemistry, biochemical assay development and profiling of drug candidates—as well as the development of array-based screening techniques. She has a great deal of expertise in array-based screening of pharmaceutical target proteins and antibodies using small-molecule and peptide microarrays. Sekul is co-inventor and owner of several patents for peptide and small-molecule drugs. She joined PEPperPRINT in 2012 as head of research and development and is responsible for the exploration and implementation of new applications for peptide microarrays.
What to see out of AACR
By Jeffrey Bouley
Taking a whirlwind—and admittedly very cursory—tour of news from the annual meeting of the American Association for Cancer Research (AACR) held in mid-April in Chicago, here are some examples of cancer research and cancer technology highlighted at the meeting.
Culturing CTCs for in-vitro drug testing
SURREY, U.K.—ANGLE plc, a liquid biopsy company, announced that results presented by one of the leading U.S. cancer centers at AACR 2018 demonstrated a workflow for culturing circulating tumor cells (CTCs) using ANGLE’s Parsortix system.
The research undertaken by the Robert H Lurie Comprehensive Cancer Center and the Feinberg School of Medicine at Northwestern University in Chicago reportedly has, for the first time, developed an optimized workflow for the recovery and culturing of CTCs from a simple blood test to produce an effective ex-vivo culture of the individual patient’s cancer cells. The team of investigators, led by Dr. Massimo Cristofanilli, focused on demonstrating the capability to interrogate and test cancer cells collected from patients with advanced breast cancer.
According to ANGLE, this achievement was only possible because the epitope-independent—that is to say that it does not use antibodies—patented microfluidic process used by the Parsortix system for CTC enrichment harvests undamaged living CTCs, which can then be cultured.
This is said to be the first time that an optimized workflow has been presented to culture CTCs ex vivo, a goal of many research groups for some time—but unachievable because the methods of CTC isolation used yield low numbers of only partially purified CTCs that are fixed before isolation (hence killed), damaged during the cell purification process or irreversibly immobilized on an adherent matrix.
“The ability to recover, culture and interrogate cancer cells expands our possibility to advance precision medicine in breast cancer patients,” said Cristofanilli, who is associate director of translational research at the Robert H Lurie Comprehensive Cancer Center. “We believe that the optimization of the workflow utilizing the Parsortix system to produce ex-vivo cultures of CTCs is already opening up a new frontier in the management of breast cancer, by allowing the testing of treatments in a ‘predictive in-vitro system’ truly representative of the patient’s disease and improving our ability to select agents and predict efficacy. Widely adopted, this approach has the potential to transform the way we treat cancer patients.”
Successful production of AML DC vaccines
PLANEGG, Germany—Researchers from Germany’s Medigene AG and Norway’s Oslo University Hospital presented a poster at AACR 2018 on the generation of dendritic cell (DC) vaccines for Medigene’s ongoing Phase 1/2 clinical trial with acute myeloid leukemia (AML) patients.
Dr. Kai Pinkernell, chief medical officer and chief development officer of Medigene, commented: “These results clearly demonstrate the feasibility and robustness of our production protocol for high numbers of clinical-grade TLR7/8-polarized fast mature DCs from heavily pretreated AML patients, allowing for long-term vaccination of trial subjects.”
A total of 20 patients averaging the age of 59 (range 24 to 73 years) were recruited to this ongoing trial. For vaccine production, autologous apheresis material was collected from each patient. Following isolation of DC precursor cells, fast DC generation was performed using Medigene’s proprietary TLR7/8-agonist containing maturation cocktail. The final DC vaccine product was cryopreserved in multiple aliquots prepared to deliver five million to 10 million cells per vaccine dose.
Successful production runs of dendritic cells for vaccination were achieved for all 20 AML patients. An additional apheresis for a second production run in order to generate sufficient vaccine doses for the intended treatment period was performed during the trial for only four out of the 20 patients enrolled in the trial.
The production runs were performed at the Department of Cellular Therapy at the Oslo University Hospital.
PEN-866 in combo with PARP inhibitors in preclinical models
WATERTOWN, Mass.—Tarveda Therapeutics Inc., a clinical-stage biopharmaceutical company discovering and developing Pentarins as a new class of potent and selective cancer medicines, presented data on the efficacy of PEN-866, a novel miniature drug conjugate comprised of a heat shock protein 90-targeting ligand attached through a cleavable linker to SN-38, when combined with poly ADP ribose polymerase (PARP) inhibitors in preclinical models of human cancer. SN-38 is a potent topoisomerase 1 inhibitor, and is the active metabolite of irinotecan.
The data presented evaluated the use of PEN-866 in combination with PARP inhibitors as an approach to overcoming limitations of PARP inhibitor monotherapy, such as dose-limiting toxicities, in preclinical models of human cancer. In efficacy studies carried out in both BRCA mutant and BRCA wildtype tumor xenografts, combinations of PEN-866 and PARP inhibitors resulted in greater efficacy than that of the monotherapy in both tumor types.
“[The data showed that] when combined with PARP inhibitors, PEN-866 could avert the dose-limiting toxicities often seen when PARP inhibitors are combined with other anticancer therapies,” said Dr. Richard Wooster, president of research and development and chief scientific officer of Tarveda. “The high levels of accumulation and retention of the combination of PEN-866 and a PARP inhibitor in xenograft tumors demonstrate the potential for greater efficacy compared to single-agent therapy.”
PEN-866’s linker cleavage provides sustained release of SN-38 at a high local tumor concentration leading to DNA damage and apoptosis of tumor cells, which results in broad antitumor activity in a range of preclinical xenograft models. When PEN-866 is administered in combination with PARP inhibitors, the inhibitors reduce DNA repair activity in tumor cells, enabling PEN-866 to maximize its efficacy in damaging cancer cell DNA. A pharmacodynamic assessment of DNA damage performed in tumors responsive to the combination treatment further demonstrated the efficacy of the therapy.
Early data on BriaCell therapeutic for breast cancer
BERKELEY, Calif. & VANCOUVER, British Columbia—BriaCell Therapeutics Corp., an immuno-oncology-focused biotechnology company with a proprietary targeted immunotherapy technology, presented two posters at AACR 2018 highlighting the most recent scientific and clinical findings for its lead product candidate—SV-BR-1-GM, also known as Bria-IMT.
The poster presentation provided data from the Bria-IMT Phase 1/2a clinical trial and demonstrated that Bria-IMT, delivered as a monotherapy regimen along with other immune system modulators, generated immune responses, as well as tumor reduction in some patients. Specifically, the data showed the following:
The regimen produced clinically relevant regression of metastases in patients with advanced stage IV breast cancer
Responses were rapid and were fully developed by three months and durable at six months
The responses developed despite previous chemotherapy with multiple different regimens
The regimen appeared to be safe and well tolerated
The tumor reduction responses appeared most pronounced in patients who match with Bria-IMT at one or more HLA loci.
“We are intrigued by the initial data indicating safety and efficacy of Bria-IMT in patients with advanced breast cancer, and we look forward to [using] these findings in the development of Bria-OTS, our off-the-shelf personalized immunotherapy treatment for advanced breast cancer, which is expected to cover about 95 percent of the patient population,” stated Dr. Bill Williams, BriaCell’s president and CEO.
AXL inhibitor bemcentinib could improve efficacy of checkpoint inhibitors
BERGEN, Norway—BerGenBio ASA, a clinical-stage biopharmaceutical company developing novel, selective AXL kinase inhibitors for multiple cancer indications, announced that promising preclinical data with its lead AXL inhibitor bemcentinib (formerly BGB324) was presented in a poster at AACR 2018, showing bemcentinib’s potential to reverse tumor immune suppression and enhance immune checkpoint inhibitor efficacy.
According to the authors, bemcentinib targets immune suppression mechanisms in the tumor microenvironment that improve immunotherapy in murine tumor models of non-small cell lung (NSCLC), triple-negative breast (TNBC) and pancreatic cancer. Bemcentinib treatment reduces myeloid-derived suppressor cells, and the altered immune landscape is associated with increased tumor infiltration of T cells (NK and CD8+) and enhanced therapy responses.
A validated AXL immunohistochemistry (IHC) method for use on patient samples to identify the presence of AXL on tumor cells and immune cells in the tumor microenvironment was presented. The authors reported that across 92 banked tumor biopsies from patients with TNBC or NSCLC, 70 percent were found to stain positive for AXL using this IHC method. The IHC method is now in use to analyze biopsies taken in connection with the company’s Phase 2 combination trials of bemcentinib with Keytruda in patients with advanced NSCLC or TNBC.
Synthetic macromolecules kill multidrug-resistant cancer cells
ARMONK, N.Y.—IBM noted in a blog post recently that while five-year survival rates have been steadily improving over the last three decades to nearly 70 percent, according to the American Cancer Society, challenges remain with such existing cancer therapies as radiation therapy and chemotherapy—healthy cells can be killed along with the cancerous ones and, in the case of chemo, drug resistance can become a problem, both with existing drug-resistant cancer cells as well as induced resistance.
To address such issues, scientists at IBM Research–Almaden in San Jose, Calif., together with Singapore’s Institute of Bioengineering and Nanotechnology, Institute of Molecular and Cell Biology and Genome Institute of Singapore developed a new class of synthetic polymer designed to selectively kill cancer cells, while ignoring healthy cells. In testing, cancer cells were unable to develop resistance to this new class of macromolecules, which might also be effective against cancer cells that are resistant to other drugs.
In a study published in the Journal of the American Chemical Society, researchers demonstrated that a macromolecule containing positively charged components was able to bind to the negatively charged surfaces of the cancer cells. Another portion of the macromolecule assimilated into the cell membrane, poking holes in the cancer cell and destroying it from within. In early tests, the macromolecule proved successful in: combating drug-resistant cancer cells and cancer stem cells, preventing cancer cell migration and defying drug resistance after multiple treatment applications.
The macromolecules were designed to self-assemble into core-shell structured nanoparticles, which typically accumulate in tumor tissues by passing through leaky blood vessels in the tumor microenvironment.
The study builds on multiple recent studies showing the potential of macromolecules to fight viruses and drug-resistant bacteria.
Researchers identify crucial enzyme driving breast cancer
BUFFALO, N.Y.—Looking to identify new strategies to prevent breast cancer recurrence, a research team led by Dr. Subhamoy Dasgupta, an assistant professor of oncology in the Department of Cell Stress Biology at Roswell Park Comprehensive Cancer Center, has identified two key proteins involved in glucose metabolism that could be targeted to prevent breast cancer metastasis and recurrence. The team’s findings were published in the journal Nature.
As Roswell Park notes, rapid growth and proliferation are hallmarks of cancer cells, which require a large amount of glucose to meet their energy needs. Because the majority of advanced breast tumors are notably dependent on glucose metabolism, strategies that alter the metabolic pathways of cancer cells can be used to improve outcomes and prevent metastasis or recurrence in patients with breast cancer.
Working with Dr. Bert O’Malley and other researchers from Baylor College of Medicine in Houston, where this work originated, Dasgupta screened more than 600 proteins and identified PFKFB4, an enzymatic protein involved in the glucose metabolic pathway, as the strongest activator of SRC-3, a protein known to drive cancer progression and metastasis. Breast cancer patients whose tumors express SRC-3 generally have a poor prognosis, suggesting that therapies targeting these two proteins or blocking their interaction could have a broad and significant impact on breast cancer treatment.
“The enzyme PFKFB4 acts as a molecular fulcrum stimulating the activation of SRC-3, which promotes growth of very aggressive metastatic tumors,” explained Dasgupta, first author on the study. “Remarkably, we also found that the expression of PFKFB4 is significantly enhanced across all types of breast cancer. This research suggests that the development of strategies targeting the PFKFB4-SRC-3 pathway could be used to prevent the growth, recurrence and spread of many, if not all, types of breast cancer tumors.”
The study was titled “Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer.”
Boehringer Ingelheim and OSE announce immuno-oncology partnership
INGELHEIM, Germany & NANTES, France—April saw Boehringer Ingelheim and biotech OSE Immunotherapeutics announce a collaboration and exclusive worldwide collaboration and license agreement to jointly develop OSE-172, a SIRP-alpha antagonist targeting myeloid lineage cells.
SIRP-alpha is a receptor expressed by myeloid lineage cells such as dendritic cells (DCs), tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). In targeting SIRP- alpha, the OSE-172 monoclonal antibody reportedly prevents the ligand CD47 from binding to and triggering the cellular inhibitory effects of SIRP-alpha.
OSE-172 has the potential to enhance antitumor immunity by improving T cell activity through enhancement of DC antigen presentation functionality, potentiating the phagocytic and inflammatory properties of macrophages in the tumor microenvironment and enabling differentiation of MDSCs to an effector state.
“This partnership with Boehringer Ingelheim is a real recognition of the value of our innovative approach to treating cancer and will create an exciting new alliance to fuel the Phase 1 development of OSE-172,” said Dr. Dominique Costantini, CEO of OSE Immunotherapeutics. “Boehringer Ingelheim’s expertise and insights will be invaluable as we step up the clinical development and work to commercialize this new treatment paradigm.”
“We are excited to partner with OSE Immunotherapeutics to develop this promising, novel cancer immunotherapy,” added Dr. Jonathon Sedgwick, global head of the Cancer Immunology & Immune Modulation Research program at Boehringer Ingelheim. “A key area of focus is the identification of drugs that target myeloid cell immune regulatory receptors, of which SIRP-alpha is a leading example. We are dedicated to developing groundbreaking, first-in-class therapies that can transform the lives of patients and help win the fight against cancer.”
Boehringer Ingelheim has acquired the global rights to develop, register and commercialize OSE-172 as part of its continued commitment to research and innovation in immuno-oncology. Under the terms of the agreement, OSE Immunotherapeutics will receive a €15-million upfront payment from Boehringer Ingelheim, and potentially additional short-term milestones of up to €15 million upon initiation of a Phase 1 clinical study. OSE Immunotherapeutics stands to receive more than €1.1 billion upon reaching pre-specified development, commercialization and sales milestones, plus royalties on worldwide net sales.
Tyme and JAF announce sarcoma treatment collaboration
NEW YORK—Tyme Technologies Inc., a clinical-stage oncology company, announced this spring that it is collaborating with The Joseph Ahmed Foundation (JAF) to provide treatment for metastatic sarcomas. The collaboration will focus on children and young adults with bone or soft tissue sarcomas, with an initial focus on Ewing’s sarcoma. Sarcomas are rare forms of cancer that have poor prognosis at the metastatic stage, with most treatment options demonstrating limited efficacy and high toxicity.
Two Ewing’s sarcoma patients have previously been treated with Tyme’s SM-88 therapy under compassionate use programs, both of whom achieved a complete or partial response with no drug-related severe adverse events. Under this new collaboration, Tyme will supply SM-88 at no cost and JAF will provide resources for physicians to perform investigator-sponsored trials.
“JAF was founded to honor the memory of our son, Joseph, by fundraising for research and helping discover new treatments for sarcoma that will allow young people to feel young rather than like cancer patients,” said Junny Ahmed, co-founder of JAF. “Joseph had metastatic Ewing’s sarcoma and was very sick after treatment on chemotherapy. We were told he had limited to no therapeutic options. He started SM-88 monotherapy and not only had a partial response, but also felt well enough to participate in a ‘Steps for Joe’s Cure’ walk (a fundraising event in Joseph’s honor) and attend his prom. At a minimum, we just want to give other families that same opportunity.”