Tag Archives: #livercancer

Radio-wave Therapy Is Safe for Liver Cancer Patients and Shows Improvement in Overall Survival (Medicine)

Researchers at Wake Forest School of Medicine have shown that a targeted therapy using non-thermal radio waves is safe to use in the treatment of hepatocellular carcinoma (HCC), the most common type of liver cancer. The therapy also showed a benefit in overall survival.

The study findings appear online in 4Open, a journal published by EDP Sciences.

“HCC accounts for nearly 90% of all liver cancers, and current survival rates are between six and 20 months,” said Boris Pasche, M.D., Ph.D., chair of cancer biology and director of Wake Forest Baptist’s Comprehensive Cancer Center. “Currently, there are limited treatment options for patients with this advanced liver cancer.”

For the study researchers used a device called TheraBionic P1, invented by Pasche and Alexandre Barbault of TheraBionic GmbH in Ettlingen, Germany, that works by delivering cancer-specific, amplitude-modulated radiofrequency electromagnetic fields (AM RF EMF) programmed specifically for HCC. 

The frequencies used are specific to the patient’s type of cancer as identified through tumor biopsies or blood work, Pasche said.

Pasche and Barbault discovered radio frequencies for 15 different types of cancer, as previously reported in a study published in 2009 in the Journal of Experimental & Clinical Cancer Research.

TheraBionic P1 is a hand-held device that emits radio frequencies via a spoon-shaped antenna, which is placed on the patient’s tongue during treatment and is administered three times a day for one hour to deliver low levels of radiofrequency electromagnetic fields throughout the patient’s body.

In previous studies, the device, which received breakthrough designation from the FDA in 2019, was shown to block the growth of liver cancer cells in the body without damaging healthy cells. 

For the current study, 18 patients with advanced HCC participated and received treatment with the device. Researchers also analyzed previously published data on 41 patients from a phase II study and historical controls from earlier clinical trials. 

“Our findings show an improvement in overall survival of more than 30% in patients with well-preserved liver function and also in those with more severe disease,” Pasche said.

Researchers also tracked side effects, and no patients stopped TheraBionic P1 treatment because of adverse reactions.

“We’re encouraged by these initial findings,” Pasche said. “Our study shows a benefit in overall survival, and the treatment isn’t associated with any significant side effects.”

Support for this study was provided by TheraBionic Inc. and funds from Wake Forest Baptist’s Comprehensive Cancer Center. 

Pasche noted that the study does have several limitations because of the small sample size and “selection bias inherent in the use of historical control data.”

However, two additional clinical trials are underway and are being led by William Blackstock, M.D., chair of radiation oncology at Wake Forest Baptist’s Comprehensive Cancer Center. One is a single-center study to assess the safety and effectiveness of the TheraBionic device in combination with Regorafenib, a chemotherapy drug, as a second-line treatment. Another multicenter, double-blind, randomized study comparing TheraBionic with placebo will assess the safety and effectiveness of the device as a third-line therapy in the treatment of advanced HCC.

Pasche holds stock in TheraBionic Inc. and TheraBionic GmbH. He is chairman of the board and CEO of TheraBionic Inc. and co-CEO of TheraBionic GmbH. He is also a senior editorial board member of Life Sciences-Medicine of 4Open by EDP Sciences. These relationships are being managed per institutional policy by Wake Forest School of Medicine’s Conflict of Interest Review Committee.

Featured image: Diagram of patient using theraionic device © WBMC

Reference: Arthur W. Blackstock, Al B. Benson, Masatoshi Kudo, Hugo Jimenez, Preeya F. Achari, Callum McGrath, Volker Kirchner, Lynne I. Wagner, Nathaniel S. O’Connell, Kathy Walker, Valerie K. Pasche, Ralph D’Agostino, Alexandre Barbault, Boris Pasche. Safety and Efficacy of amplitude-modulated radiofrequency electromagnetic fields in advanced hepatocellular carcinoma. 4open, 2021; 4: 3 DOI: 10.1051/fopen/2021003

Provided by Wakeforest Baptist Medical Center

Drug Combination Gets Advanced Liver Cancer Patients to Surgery (Medicine)

Combination therapy could make curative surgery possible for some liver cancer patients who would normally not be considered for the surgery

A combination of the kinase-inhibitor drug cabozantinib and the immunotherapy drug nivolumab can make curative surgery possible in some liver cancer patients who would normally not be considered surgery candidates.

Results published July 29 in the journal Nature Cancer by researchers at the Johns Hopkins Kimmel Cancer Center describe the benefits of this drug combination. Among 15 people with hepatocellular carcinoma (HCC) in the study who could not be treated previously with surgery, the drugs allowed 12 patients to undergo successful surgical removal of their cancer. Five of these 12 patients had only 10% or less of their tumor remaining after the drug treatment.

The combination therapy offers a much-needed treatment for HCC, which makes up more than 90% of all primary liver cancers and is the fourth leading cause of cancer-related death worldwide. Fewer than 30% of HCC cases globally can be surgically resected at the time of diagnosis, either because the liver is too damaged or the cancer has spread into tissues that make surgery too difficult.

“The patients who are enrolled in this study are typically just thought of as incurable in the current conventional sense, so the fact that we saw these responses was really exciting, because this suggests this strategy could be adopted for very challenging incurable diseases,” says Won Jin Ho, M.D., assistant professor of oncology at the Johns Hopkins University School of Medicine and first author of the study.

HCC is unusual among solid-tumor cancers because there have been no systemic therapies used to treat the cancer to make it more amenable to surgery, says Mark Yarchoan, M.D., assistant professor of oncology at the Johns Hopkins University School of Medicine and senior author. “We had a hunch that there were patients who were currently incurable that we could get to a surgery who would do well, and sure enough, there was a group of patients who participated in this study who are alive today without tumor who would not have been offered surgery before.”

The findings also suggest that the drug combination could help with rates of cancer recurrence after surgery. Even among patients who have successful surgeries, the rate of recurrence can be 50% or higher. In the current study, the researchers found that the five patients who underwent surgery and had their tumors shrink significantly have remained disease free for more than 230 days so far. Four of the seven patients who did not have a significant tumor response developed disease progression between 56 and 155 days after the end of treatment.

Cabozantinib and nivolumab have been used separately and in combination to treat advanced liver cancer before, but the researchers wanted to test their use specifically to see whether they could make more patients eligible for potentially curative surgery.

“We wanted to use a combination that reflected the standard of care,” says Yarchoan, “and this combination reflected where we feel the field is going in terms of using two drugs together to try to maximize the therapeutic effects.”

All of the patients were recruited from the Kimmel Cancer Center’s Liver and Biliary Cancer Multidisciplinary Clinic, where patients are evaluated by multiple experts in surgery, pathology, medical oncology and other disciplines to come up with a comprehensive treatment plan. The multidisciplinary teamwork is good for patients but is also helpful in this type of study, Yarchoan adds. “At other institutions where you might just see a surgeon, there isn’t an opportunity to discuss adding in medicines.”

The research team took a closer look at the immune response and tumor microenvironment in blood and tissue biopsies from patients enrolled in the study to learn more about exactly how HCC responded — or didn’t respond — to the combination treatment. A technique called imaging mass cytometry allowed the clinicians to observe multiple types of cells at once, “and really understand their relationships with one another,” says Ho.

For instance, the researchers note that a distinct aggregation of immune B cells was indicative of a response to cabozantinib and nivolumab, supporting a strong antitumor response. The technique also helped the researchers see how the proximity of B cells and T cells to some macrophage immune cells with an immunosuppressive effect was characteristic of tumors that were resistant to the combination treatment.

Going forward, this type of in-depth look at the tumor microenvironment could help clinicians search for drugs that promote a B cell response or reprogram immunosuppressive immune cells in the liver to make them more responsive to therapy, the researchers note.

Qingfeng Zhu, Jennifer Durham, Aleksandra Popovic, Stephanie Xavier, James Leatherman, Aditya Mohan, Guanglan Mo, Shu Zhang, Nicole, Gross, Soren Charmsaz, Brad Wilt, Ihab R. Kamel, Matthew Weiss, Benjamin Philosophe, Richard Burkhart, Whilliam Burns, Chris Shubert, Aslam Ejaz, Atul Deshpande, Ludmila Danilova, Genevieve Stein-O-Brien, Elizabeth Sugar, Daniel A. Laheru, Robert A. Anders, Elana J. Fertig, and Elizabeth Jaffee from Johns Hopkins and Dongxia Lin and Derek Quong from Fluidigm Corporation also participated in the research.

The work was supported by the Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, Emerson Collective Cancer Research Fund; grants P50 CA062924), P30 CA006973, U01 CA212007 and U01 CA21200 from the National Institutes of Health, Exelixis and Bristol Myers Squibb.

Ho is a co-inventor of patents with potential for receiving royalties from Rodeo Therapeutics/Amgen, received consulting fees for Exelixis, and receives research support from Sanofi. Anders reports receiving a commercial research support from Bristol-Myers Squibb and is a consultant/advisory board member for Bristol-Myers Squibb, Merck, AstraZeneca, Incyte and RAPT Therapeutics. Jaffee reports receiving a commercial research grant from Bristol-Myers Squibb and Aduro Biotech, and is a consultant/advisory board member for Lustgarten Foundation, Parker Institute for Cancer Immunotherapy, CStone, Dragonfly, Genocea, Achilles and Adaptive Biotechnologies, and Co-Founder of Abmeta Biotech. Yarchoan reports receiving research grants from Incyte, Bristol-Myers Squibb, and Exelixis, and is a consultant for AstraZeneca, Eisai, Exelixis, and Genentech.

Featured image: Representative staining of the immune tumor microenvironment from a responder patient using imaging mass cytometry. Credit: Won Jin Ho, M.D.

Reference: Won Jin Ho et al, Neoadjuvant cabozantinib and nivolumab convert locally advanced hepatocellular carcinoma into resectable disease with enhanced antitumor immunity, Nature Cancer (2021). DOI: 10.1038/s43018-021-00234-4

Provided by Johns Hopkins University School of Medicine

Toward The First Drug To Treat A Rare, Lethal Liver Cancer (Medicine)

New drugs to eliminate fibrolamellar tumors cells, pictured here, were identified using an expedited approach.

Treatment options for a deadly liver cancer, fibrolamellar carcinoma, are severely lacking. Drugs that work on other liver cancers are not effective, and although progress has been made in identifying the specific genes involved in driving the growth of fibrolamellar tumors, these findings have yet to translate into any treatment. For now, surgery is the only option for those affected—mostly children and young adults with no prior liver conditions.

Sanford M. Simon and his group understood that patients dying of fibrolamellar could not afford to wait. “There are people who need therapy now,” he says. So his group threw the kitchen sink at the problem and tested over 5,000 compounds, either already approved for other clinical uses or in clinical trials, to see whether any of the compounds could be repurposed to treat fibrolamellar. The team ultimately discovered a few classes of therapeutics that destroy fibrolamellar tumor cells growing in mice. Their findings are published in Cancer Discovery.

“We decided to be completely agnostic about what we thought would work—we tried everything,” says Simon, head of the Laboratory of Cellular Biophysics. “To our surprise, we found a few compounds that work really well.”

Faster drug discovery

In an ideal world, scientists perform extensive experiments to identify the perfect therapeutic target for a disease, then test a suite of drugs in model systems to pinpoint promising treatment options to hit the chosen target. The Simon lab is undergoing such experiments, but this process can take years, and the children and young adults who are sick now of fibrolamellar will likely never see the fruits of such labors.

So Simon took a parallel, expedited approach. After testing an extensive library of drugs on fibrolamellar tumor cells grown in mice over the course of several months, his team identified a few novel classes of therapeutics that appear to effectively kill fibrolamellar tumor cells, and further experiments provided some molecular explanations for why these drugs are so effective against a disease that has, until now, baffled physicians who treat liver cancer.

“Up to this point I’ve had to tell patients that we don’t have any medicines that are proven to work,” says Michael V. Ortiz, a pediatric oncologist at Memorial Sloan Kettering Cancer Center and a collaborator on the study. “It’s really thrilling that we finally have some promising drugs to go after in clinical trials. And, since each individual responds differently, it’s particularly exciting that we had multiple hits, which we can now test in combination with one another.”

Treatment tailored for one

Building on these initial findings, Simon and his colleagues tested the compounds on human cells taken directly from patient tumors. They were able to test the cells against their lineup of drug candidates after growing them for only a few days, obtaining results similar to those observed in cells that took months to grow.

“Within three days, we can have therapeutically informative data, which is much faster than previous methods allowed,” says Gadi Lalazar, an instructor in clinical investigation in the Simon laboratory and first author on the study. “Although there are some logistical hurdles and additional verification is needed, this could potentially be transformative for treating certain cancers.”

The findings suggest that it may be unnecessary to screen new cancer drug candidates in cells grown in mice before testing them on human cells—an extra step that can cost cancer researchers many months. Given these results, physicians may soon be able to biopsy cells from a patient’s tumor, subject those cells to a bevy of drug candidates until they find the most effective compound for that specific patient, and have a treatment plan ready in a matter of days—potentially transforming the landscape of precision medicine.

Advances in precision medicine

Simon’s recent work was inspired by the 2015 precision medicine initiative begun in the Obama administration, which promised to change the face of medicine with a targeted approach, tailored to a patient’s unique genetic composition, lifestyle, and environment.

“You don’t want to give everyone with a limp the same treatment—you want it ‘precisely targeted’ based on whether they have twisted their ankle, broken a bone, or just have a splinter,” says Simon.

Over the past six years, Simon has developed a series of model systems to help identify molecules known to drive cancers, known as oncogenes. But the key to applying precision medicine to cancer, Simon realized, is not blindly testing drugs against mutations or abnormally expressed genes—it’s performing functional screenings that ask what drugs actually have an impact on the tumor in question.

The results of Simon’s approach have now yielded the first therapeutics shown to eliminate fibrolamellar tumor cells, and new hope for people suffering from a deadly disease.

Reference: Gadi Lalazar, David Requena, Lavoisier Ramos-Espiritu, Denise Ng, Patrick D Bhola, Ype P. de Jong, Ruisi Wang, Nicole J.C. Narayan, Bassem Shebl, Solomon Levin, Eleftherios Michalidis, Mohammad Kabbani, Koen O.A. Vercauteren, Arlene M Hurley, Benjamin A Farber, William J Hammond, James A Saltsman, Ethan M Weinberg, J. Fraser Glickman, Barbara A Lyons, Jessica Ellison, Erik Schadde, Martin Hertl, Jennifer L Leiting, Mark J Truty, Rory L Smoot, Faith Tierney, Tomoaki Kato, Hans-Guido Wendel, Michael P. LaQuaglia, Charles M Rice, Anthony Letai, Philip Coffino, Michael S Torbenson, Michael V Ortiz and Sanford M Simon, “Identification of Novel Therapeutic Targets for Fibrolamellar Carcinoma Using Patient Derived Xenografts and Direct from Patient Screening”, Cancer Discovery, 2021. DOI: 10.1158/2159-8290.CD-20-0872

Provided by Rockefellar University

Salk Team Reveals Never-before-seen Antibody Binding, Informing Both Liver Cancer and Antibody Design (Biology)

Multi-institute collaboration uses X-ray crystallography and recombinant antibodies to uncover workings of an elusive molecule central to human health

In structural biology, some molecules are so unusual they can only be captured with a unique set of tools. That’s precisely how a multi-institutional research team led by Salk scientists defined how antibodies can recognize a compound called phosphohistidine—a highly unstable molecule that has been found to play a central role in some forms of cancer, such as liver and breast cancer and neuroblastoma.

These insights not only set up the researchers for more advanced studies on phosphohistidine and its potential role in cancer, but will also enable scientists to manipulate the shape and atomic makeup of the antibodies’ binding sites in order to design ever more efficient antibodies in the future. The study was published in the Proceedings of the National Academy of Sciences on February 5.

“We are excited that these new antibody structures reveal novel principles of antigen binding. Now we can redesign these antibodies and engineer their properties to make them more efficient,” says Tony Hunter, Renato Dulbecco Chair and American Cancer Society Professor at Salk and the paper’s senior author. “This work may also provide other scientists with phosphohistidine antibodies that better suit their research purposes.”

Amino acids are joined together in precise sequences to form proteins, and several of them can undergo chemical transformations that can change the activity of the protein for better or worse. One such transformation is a process called phosphorylation, when a compound called phosphate is added to an amino acid, changing its shape and charge. Previously, Hunter showed that phosphorylation on the amino acid tyrosine can drive cancer progression, a discovery that led to numerous anticancer drugs. More recently, Hunter turned his attention to phosphorylation of the amino acid histidine (which creates phosphohistidine), suspecting that the process might also play a role in human disease.

Hunter developed a suite of antibodies able to bind to phosphohistidine in proteins, and used chemically stabilized phosphohistidine analogues to develop a series of monoclonal antibodies that could recognize these forms. The next step was to understand exactly how the antibodies are able to bind to phosphohistidine. This led Hunter to collaborate with Ian Wilson, the Hansen Professor of Structural Biology at the Scripps Research Institute and a world-renowned expert in using protein crystallography to define antibody structures, to study the structures of the phosphohistidine antibodies.

“My long-term colleague Tony and I have been collaborating on this project for the past seven years,” says Wilson. “We have obtained new insights into how antibodies can evolve to recognize phosphates linked to proteins, which is very satisfying.”

To find out how phosphohistidine is recognized, they needed to image their antibodies in the act of binding the phosphohistidine, and so formed crystals between each antibody bound to a phosphohistidine peptide.

“To understand the molecular interactions between the antibodies and phosphohistidine, we needed to look at them in great detail,” says first author Rajasree Kalagiri, a Salk postdoctoral researcher and expert in X-ray crystallography. “Once we got the antibodies to form crystals, we bombarded those crystals with X-rays to obtain a diffraction pattern. We then applied methods that transform the diffraction pattern into a three-dimensional electron density map, which was then used to discern the atomic structure of the antibodies.”

The two types of antibody crystal structures solved by the team revealed exactly how different amino acids are arranged around the phosphohistidine to bind it tightly. Their five structures more than double the number of phospho-specific antibody structures previously reported, and provide insights into how antibodies recognize both the phosphate and the linked histidine. They also reveal at a structural level how the two types of antibody recognize different forms of phosphohistidine, and this will allow the scientists to engineer improved antibodies in the future.​

Other authors on the study were Jill Meisenhelder and Stephen R. Fuhs of Salk; Robyn Stanfield of the Scripps Research Institute; and James J. La Clair of the University of California San Diego.

This work was funded by the National Cancer Institute of the National Institutes of Health; the Leona M. and Harry B. Helmsley Charitable Trust; and the Skaggs Institute for Chemical Biology at The Scripps Research Institute.

Featured image: A structural snapshot of a phosphohistidine analogue (ball and stick model) nestled at the interface between different areas (green, brown) of a phosphohistidine antibody. Such structures provide insights into the molecular properties of the antibodies, which makes them useful for revealing elusive phosphohistidine-containing proteins in cells. © Salk Institute

Reference: Rajasree Kalagiri, Robyn L. Stanfield, Jill Meisenhelder, James J. La Clair, Stephen R. Fuhs, Ian A. Wilson, and Tony Hunter, “Structural basis for differential recognition of phosphohistidine-containing peptides by 1-pHis and 3-pHis monoclonal antibodies“, PNAS, 2021.

Provided by Salk Institute

Drug ‘Breakthrough’ Gives Longest-ever Survival in Nonresectable Liver Cancer Patients (Medicine)

The IMbrave150 trial found median overall survival was 19.2 months in patients treated with atezo+bev vs 13.4 months for those treated with sorafenib alone, the current standard treatment

The IMbrave150 trial found median overall survival was 19.2 months in patients treated with atezo+bev vs 13.4 months for those treated with sorafenib alone, the current standard treatment (HR, 0.66 [95% CI, 0.52-0.85]; P=0.0009). Survival at 18 months was 52% with atezo+bev and 40% in patients treated with sorafenib.

All patients in the trial had nonresectable HCC – the most common form of liver cancer – and had not previously been treated with systemic therapy. A total of 501 patients were treated in the multicentre, open label, randomised controlled trial and the new follow-up figures confirm the superiority of the atezo+bev combination over sorafenib in this group of patients with HCC.

Atezolizumab is an immune checkpoint inhibitor drug, which helps the immune system hunt down and destroy cancer. Bevacizumab is a targeted monoclonal antibody therapy that starves tumours of their blood supply by preventing endothelial growth but also enhances the immune effects of atezolizumab.

The new data, presented today at the European Association for the Study of the Liver (EASL) Liver Cancer Summit 2021, follows the initial publication of trial data[i] with 8.6 months of follow-up which found survival at 12 months was 67.2% with atezo+bev, compared to 54.6% in those treated with sorafenib. This new post-hoc descriptive overall survival analysis included 12 months of additional follow-up from the primary analysis.

Prof. Richard Finn, lead author of the study, commented, “IMbrave150 showed consistent clinically meaningful treatment benefit and safety with an additional 12 months of follow-up. The combination provides the longest survival seen in a front-line Phase III study in advanced HCC, confirming atezo+bev as a standard of care for previously untreated, unresectable HCC.”

“These are highly significant findings for the treatment of patients with HCC. Many thousands of patients worldwide could benefit from this treatment and it can be considered a major breakthrough – the first improvement in treatment for these types of cases in 13 years and a treatment long awaited by doctors.”

The trial enrolled systemic treatment-naive patients with unresectable HCC, ?1 measurable untreated lesion (RECIST 1.1), Child-Pugh class A liver function and ECOG PS 0/1. Patients were randomised 2:1 to atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sorafenib 400 mg bid until unacceptable toxicity or loss of clinical benefit per investigator. Patients were required to have an upper endoscopy within 6 months of starting the study, to assess for high-risk varices.

Survival benefit with atezo+bev vs sorafenib was generally consistent across subgroups and with the primary analysis. The updated objective response rate (ORR; 29.8% per RECIST 1.1) with atezo+bev was in line with the primary analysis, with more patients achieving complete response (CR; 7.7%) than previously reported. Safety was consistent with the primary analysis, with no new signals identified.

“We now need to understand what is next in front-line liver cancer and how will we build on this data to further improve outcomes beyond the 19.2 months we described. Additionally, we need to evaluate the efficacy for this regimen in earlier stages of HCC.”

Featured image: Digital Liver Cancer Summit 2021 © EASL

Reference: Richard S. Finn, M.D., Shukui Qin, M.D., Masafumi Ikeda, M.D., Peter R. Galle, M.D., et al., for the IMbrave150 Investigators, “Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma”, N Engl J Med 2020; 382:1894-1905 DOI: 10.1056/NEJMoa1915745 https://www.nejm.org/doi/full/10.1056/NEJMoa1915745

Provided by Spink Health

Discovery of a New Approach to Inhibiting a Highly Treatment-refractory Liver Cancer (Medicine)

The approach could pave the way for combination therapies, including chemotherapy and immune checkpoint blockade.

Reprogramming the rich connective tissue microenvironment of a liver cancer known as intrahepatic cholangiocarcinoma (ICC) inhibits its progression and resistance to standard chemotherapy in animal models, researchers from Massachusetts General Hospital (MGH) have found. This new treatment for a disease with extremely poor outcomes uses antibodies to block placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, which has been widely studied for its role in new vessel formation in cancers. PlGF is highly expressed in ICC compared to normal liver tissue, and blocking it reduces the production of connective tissue while increasing the efficacy of chemotherapy and survival in mice with ICC. These findings were reported in Gut, the journal of the British Society of Gastroenterology.

“We were able to demonstrate that PlGF is a mediator of ICC progression, and that antibody blockade of PlGF in ICC models inhibited the activity of cancer-associated fibroblasts (CAFs), which produce connective tissue and also provide ICC cells with pro-survival and pro-invasion signals,” says Dan G. Duda, DMD, PhD, director of Translational Research in GI Radiation Oncology at MGH, and senior author of the study. “Our findings suggest that PlGF inhibition is a potential therapeutic target that could have implications for other emerging combination therapies that have shown promise against ICC, a largely intractable disease with a dismal prognosis.”

ICC is an aggressive cancer of the liver with a five-year survival rate of 15% for patients with early-stage disease, and 6% for those with metastases to regional lymph nodes. The cancer is characterized by vascular abnormalities, abundant connective tissue (known as desmoplasia) produced by activated CAFs, and few therapeutic options. Systemic chemotherapy using gemcitabine and cisplatin remains the standard of care for patients with advanced ICC, but the benefits are limited. “New therapies are urgently needed as incidence of ICC grows at 3% a year in the U.S. and worldwide,” emphasizes Duda.

The MGH study was inspired by previous research by Duda and Rakesh K. Jain, PhD, director of the Edwin L. Steele Laboratories for Tumor Biology at MGH, and a pioneer in the fields of tumor microenvironment and cancer therapy, that identified PlGF as a potential target to inhibit the growth and spread of medulloblastoma, the most common pediatric malignant brain tumor. Their groundbreaking research demonstrated high expression of the PlGF receptor neuropilin 1 (Nrp1) in medulloblastoma and found that PlGF/Nrp1 blockade resulted in tumor regression, decreased metastasis, and increased survival in mice. PlGF blockade using antibodies has been tested in a phase 1 clinical trial (ClinicalTrials.gov Identifier: NCT02748135) with final results to be reported later this year.

“Our prior work led us to study other cancers where PlGF might play a pivotal role,” notes Duda. “We found that PlGF levels were also elevated in CAFs and circulating blood plasma in ICC patients, and were associated with disease progression.” Investigation in mouse models further revealed that PlGF blockade reduced desmoplasia and tissue stiffness, which are determinants of tumor aggressiveness and resistance to treatment. Consequently, the antibody blockade re-opened collapsed tumor vessels and improved blood perfusion and chemotherapy efficacy, while reducing ICC cell invasion and increasing survival in mice. “In effect, we reprogrammed the hypoxic tumor microenvironment, which could have major implications for novel combination therapies targeting ICC or other highly desmoplastic tumors, such as pancreatic cancer,” explains Jain, co-author of the latest study.

Such a systemic approach could enhance the efficacy of standard chemotherapy but also radiation therapy or immune checkpoint inhibitors, including programmed cell death 1 (PD-1) blockade – all of which have shown promise against ICC. “Our results indicate that PlGF blockade can provide a clinical strategy for growing numbers of ICC patients who have failed to see any significant improvements in treatment over the years,” says Duda.

Duda is an associate professor of Radiation Oncology at Harvard Medical School (HMS). Jain is Andrew Werk Cook Professor of Radiation Oncology (Tumor Biology) at HMS. The MGH team of researchers included lead authors Shuichi Aoki, MD, PhD, and Koetsu Inoue, MD, PhD, from the Edwin L. Steele Laboratories for Tumor Biology, and co-author Andrew X. Zhu, MD, PhD, director emeritus of Liver Cancer Research at the MGH Cancer Center and a professor of Medicine at HMS.

The study was supported by the National Institutes of Health (NIH) and the Cholangiocarcinoma Foundation.

Reference: Shuichi Aoki, Koetsu Inoue, Sebastian Klein, Stefan Halvorsen, Jiang Chen, Aya Matsui, Mohammad R Nikmaneshi, Shuji Kitahara, Tai Hato, Xianfeng Chen, Kazumichi Kawakubo, Hadi T Nia et al., “Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic Cholangiocarcinoma”, Gut, 2021. http://dx.doi.org/10.1136/gutjnl-2020-322493 https://gut.bmj.com/content/early/2021/01/11/gutjnl-2020-322493

Provided by Massachusetts General Hospital

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2020, Mass General was named #6 in the U.S. News & World Report list of “America’s Best Hospitals.”

Researchers Discover Treatment that Suppresses Liver Cancer (Oncology / Medicine)

Researchers from the University of Missouri School of Medicine have discovered a treatment combination that significantly reduces tumor growth and extends the life span of mice with liver cancer. This discovery provides a potentially new therapeutic approach to treating one of the leading causes of cancer-related death worldwide.

Guangfu Li, PhD, DVM, Department of Surgery and Department of Molecular Microbiology and Immunology at the University of Missouri School of Medicine. Credit: Justin Kelley

A cancer translational research team consisting of physicians, and basic scientists created an integrative therapy that combined minimally invasive radiofrequency ablation (RFA) with the chemotherapy drug sunitinib. Individually, each treatment has a modest effect in the treatment of liver cancer. The team hypothesized that pairing the two treatments would have a profound effect by activating an immune response to target and destroy liver cancer cells. That’s exactly what their research revealed.

“We treated tumor-bearing mice with sunitinib to suppress the cancer cells’ ability to evade detection by the immune system, then the RFA acted as a spark that ignited the anti-tumor immune response,” said principal investigator Guangfu Li, Ph.D., DVM, Department of Surgery and Department of Molecular Microbiology and Immunology.

The team tested this approach by dividing the mice into four groups: a control group, a group that received only sunitinib, a group that received only RFA, and a group that received both RFA and sunitinib. The researchers monitored tumor progression in each mouse via magnetic resonance imaging (MRI) over 10 weeks. They discovered the mice receiving combination therapy experienced significantly slowed tumor growth. The life span of the mice in the combination therapy group was significantly longer than all of the other groups.

“These results indicate that the sunitinib and RFA-integrated therapy functions as an effective therapeutic strategy that is superior to each individual therapy, significantly suppressing tumor growth and extending the lifetime of the treated mice,” said co-author Eric Kimchi, MD, MBA, Chief of Division of Surgical Oncology and General Surgery, and Medical Director of Ellis Fischel Cancer Center.

The team plans to expand their research to study the effectiveness of this combination therapy on companion dogs and eventually on humans.

“Development of an effective sunitinib and RFA combination therapy is an important contribution to the field of liver cancer treatment and can be quickly translated into clinical applications, as both sunitinib and RFA are FDA approved and are readily available cancer therapies,” said co-author Kevin F. Staveley-O’Carroll, MD, Ph.D., MBA, Chair, Department of Surgery, and Director of Ellis Fischel Cancer Center.

Reference: Xiaoqiang Qi et al, Synergizing sunitinib and radiofrequency ablation to treat hepatocellular cancer by triggering the antitumor immune response, Journal for ImmunoTherapy of Cancer (2020). DOI: 10.1136/jitc-2020-001038

Provided by University of Missouri

Combination Therapy Might Improve Outcomes in Treatment-resistant Liver Cancer (Oncology / Medicine)

A combination cancer therapy that is effective against treatment-resistant hepatocellular carcinoma (HCC) by inhibiting tumor growth and increasing survival has been identified by researchers at Massachusetts General Hospital (MGH). In a paper published in the Journal for ImmunoTherapy of Cancer, the investigators describe how the dual therapy—which combines the multikinase inhibitor drug regorafenib to “reprogram” the tumor immune microenvironment, and programmed cell death 1 (PD1) antibodies to stimulate anti-tumor immunity—improved survival in mouse models of HCC beyond what each therapy could have achieved alone.

“The holy grail of immunotherapy in treating solid cancers like HCC is to draw cancer-fighting T-cells inside the tumor,” explains Dan G. Duda, DMD, Ph.D., director of translational research in GI Radiation Oncology at MGH and senior author of the study. “We found that regorafenib delivered at the right intermediate dose tricks cancer cells into expressing a chemokine known as CXCL10 which, in turn, triggers intratumoral T-cell infiltration.”

HCC, the most common form of liver cancer, is an aggressive gastrointestinal disease that is increasing globally at more than 3% a year. It is the second deadliest form of cancer, responsible for more than 700,000 deaths annually. The encouraging news for patients is the emergence in recent years of combination therapies of anti-vascular endothelial growth factor receptor (anti-VEGFR) inhibitors along with PD1 pathway blockades.

This type of cancer develops a rich new vasculature that feeds tumor progression. This vasculature is highly abnormal, which limits the recruitment and activity of effector T-cells. Anti-VEGFR inhibitors work to control that growth in part by normalizing tumor vasculature and increasing T-cell infiltration into tumors. This concept was first advanced by study co-author Rakesh K. Jain, Ph.D., director of Steele Laboratories for Tumor Biology at MGH, and a pioneer in the fields of vascular biology and cancer therapy. PD1 inhibitors, for their part, restore the immune system’s ability to become activated and kill cancer cells by inhibiting the interaction between PD-L1, a protein on the surface of some of the malignant and non-malignant cells in HCC, and the protein PD1 on the surface of T-cells. This dual treatment strategy has shown in some clinical trials of HCC patients response rates nearly double the 15% to 20% who typically respond to anti-PD1 treatment alone.

“Combination therapy has been a major advance for the field, but it still has limitations in treating liver cancer, as evidenced by the fact so many patients experience recurrence of the disease, even as they are living longer,” says Jain. “To address treatment resistance, we suggested that an inhibitor that can target multiple kinases beyond VEGF receptors could be particularly effective. Our research teams were able to show that regorafenib has that unique capability when used at doses that induce both vascular normalization and increased expression of the chemokine CXCL10 in cancer cells. These intratumoral changes induce infiltration of T-cells into tumors where they can more effectively do their job.”

CXCL10 expression of in hepatocellular carcinoma (HCC) tissues and concentration in blood samples from patients with cancer. (A–C) CXCL10 expression by RNA-in situ hybridization (ISH) in human HCC samples; staining was scores ‘high’ (13%–17%) (A), medium (1%–11%) (B) or low (<1%) (C) fractions of HCC tumor cells with CXCL10 ISH positivity. Scale bars=500 µm. (D) Distribution of CXCL10 mRNA counts using ISH. (D) Concentration of CXCL10 in blood samples collected from HCC (n=20) and acute myeloid leukemia (AML) (n=8) patients prior to treatment. Detectable CXCL10 levels in all patients, with no significant difference between the two groups. (F) Increase of CXCL10 after 2 weeks of regorafenib treatment in patients with HCC (n=1) and AML (n=7). (G) Schematic diagram of the proposed mechanisms of benefit when using the appropriate dose of regorafenib combined with antiprogrammed cell death protein 1 (anti-PD1) therapy. Judicious dosing of regorafenib in combination with anti-PD1 antibodies can normalize HCC vessels, which results in increased drug delivery and synergy with antitumor immunity stimulated by concomitant anti-PD1 therapy. The increased CD8+ cytotoxic T lymphocyte (CTL) penetration and activation mediates this synergistic activity and is facilitated by CXCL10 expression by the cancer cells on inhibition of STAT3 phosphorylation by regorafenib. ©Shigeta et al.

Findings from the MGH study are directly informing ongoing clinical trials of regorafenib in cancer patients. Indeed, this work is highly relevant to the future development of treatments for HCC as well as other cancers that metastasize to the liver, according to Duda. “Now that our preclinical study has shown the effectiveness of dual therapy, we need to understand how to combine its components in ways that produce maximum benefit in patients,” he says. “Our work has taken a major step in that direction by demonstrating the importance of targeting the immune microenvironment of HCC while using immunotherapy against this deadly cancer.”

References: Kohei Shigeta et al, Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma, Journal for ImmunoTherapy of Cancer (2020). DOI: 10.1136/jitc-2020-001435 https://jitc.bmj.com/content/8/2/e001435

Provided by Massachusetts General Hospital

Liver Cancer Ten Times More Likely in Men With Common Genetic Disorder Haemochromatosis (Medicine/Oncology)

Men who have haemochromatosis, one of the most common genetic disorders in North America, are ten times more likely to develop liver cancer, according to a new study.

Biopsy of an iron loaded liver in a patient with hemochromatosis. The dark blue shows iron pigment within the liver. ©University of Western Ontario

Led by a team  at the University of Exeter in collaboration with Dr. Paul Adams from Western University, the research has led to renewed calls for routine early testing for the condition which causes iron overload, previously thought to be a lower-level health risk. The findings are published today in the journal JAMA.

The new study projects that more than seven per cent of men with two copies of the faulty haemochromatosis genes would develop liver cancer by age 75, compared to just 0.6 per cent in the general population. Hemochromatosis causes the body to absorb too much iron from the diet and affects one in 327 Canadians.

Reliable tests are available to identify those at risk – blood tests for measuring iron levels (serum ferritin, transferrin saturation) and genetic testing (HFE C282Y genetic blood test). Symptoms can include feeling tired all the time as well as muscle weakness and joint pains. The researchers say it can often be misdiagnosed as the signs of aging. Most of those with liver cancer develop liver damage first, often progressing to cirrhosis of the liver. Once diagnosed, the condition is easily treated by a process similar to donating blood several times a year in order to lower iron levels.

The team analyzed data from 2,890 men and women with two copies of the faulty gene (called HFE C282Y homozygous), from the UK Biobank, a large database of more than half a million British men and women recruited between 2006 and 2010 from across England, Scotland and Wales. People were aged 40 to 70 at the start of the study and were followed for a nine-year period. Twenty-one of the 1,294 men with the faulty genes studied have developed liver cancer so far, of whom 14 died due to their liver cancer. Ten of these 21 men were not diagnosed with haemochromatosis by the time they had a liver cancer diagnosis.

“The UK Biobank project is a glimpse into the future of medicine where all known genes are tested and then treatable conditions are offered treatment before serious complications develop,” said Dr. Adams, professor at Western’s Schulich School of Medicine & Dentistry, and associate scientist at Lawson Health Research Institute who has been studying haemochromatosis in Canada for more than four decades. “An early diagnosis of hemochromatosis can be treated by regular blood donation in Canada.”

Haemochromatosis is more serious in men, with women partially protected because they lose iron through menstruation and childbirth, although some younger women do develop the disease. The study found no increase in liver cancer risk in women with faulty haemochromatosis genes.

“Tragically, men with the haemochromatosis faulty genes have been dying of liver cancer for many years, but this was thought to be rare. The UK Biobank study allowed us to measure the cancer risk accurately. Finding that over seven per cent of men with the faulty genes are likely to develop liver cancer by age 75 is shocking. Fortunately, most of these cancers could be prevented with early treatment,” said David Melzer, professor at the University of Exeter Medical School, who led the research team.

The research is led by the University of Exeter Medical School in the UK, in collaboration with the University of Connecticut, Western University and South Warwickshire NHS Foundation Trust and is funded by the UK Medical Research Council.

Previously, the Exeter team found that having the haemochromatosis double faulty gene quadruples the risk of liver disease and doubles the risk of arthritis and frailty in older age groups. It also causes higher risk of diabetes and chronic pain.

References: Janice L. Atkins, Luke C. Pilling, Jane A. H. Masoli, et al., “Association of Hemochromatosis HFE p.C282Y Homozygosity With Hepatic Malignancy”, JAMA. 2020;324(20):2048-2057. doi:10.1001/jama.2020.21566

Provided by University of Western Ontario