Tag Archives: #bonecancer

Drug Doubles Down on Bone Cancer, Metastasis (Medicine)

Rice, Baylor’s ‘BonTarg’ combines breast cancer drug with bone-targeting antibody

Bone cancer is hard to treat and prone to metastasis. Research teams at Rice University and Baylor College of Medicine have a new strategy to attack it.

Chemist Han Xiao at Rice and biologist Xiang Zhang at Baylor and their labs have developed an antibody conjugate called BonTarg that delivers drugs to bone tumors and inhibits metastasis.

Their open-access study, which appears in Science Advances, shows how Xiao’s pClick technology can be used to link bone-targeting antibodies and therapeutic molecules.

Scientists are using pClick conjugation to create therapeutic antibodies that target bone cancers. The conjugate incorporates bisphosphonate molecules that bind to the bone hydroxyapatite matrix. Courtesy of Baylor College of Medicine/Rice University

In experiments, they used pClick to couple a molecule used to treat osteoporosis, alendronate, with the HER2-targeting antibody trastuzumab used to treat breast cancer and found it significantly enhanced the concentration of the antibody at tumor sites.

They reported the combination also inhibited secondary metastasis from infected organs seeded by bone tumors.

“Bone cancer is really challenging to treat, and clinical trials of different treatments have been disappointing for people with bone metastasis,” said Xiao, who joined Rice in 2017 with funding from the Cancer Prevention and Research Institute of Texas (CPRIT). “We feel our strategy is a real game changer.”

“Getting effective concentrations of drugs to bone tumors has been challenging because bones are hard, their networks of blood vessels is limited and drugs have tended to attach to adjacent healthy tissues,” Zhang said.

The new strategy employs bisphosphonates, a class of drugs typically used to treat osteoporosis. Bisphosphonates have a high binding affinity for hydroxyapatite, the main component of hard bone, and help overcome physical and biological barriers in the bone microenvironment.

They’re also amenable to binding with drugs through pClick, which uses a cross-linker to snap to specific sites on antibodies without having to re-engineer them with harmful chemicals, enzymes or ultraviolet light.

MicroCT scans of rodents show those treated with the conjugate of trastuzumab and alendronate (far right), created at Rice University and Baylor College of Medicine, fared far better than those treated with phosphate-buffered saline (PBS) or alendronate (ALN) or trastuzumab (Tras) alone 82 days after tumor implantation. (Credit: Baylor College of Medicine/Rice University)
MicroCT scans of rodents show those treated with the conjugate of trastuzumab and alendronate (far right), created at Rice University and Baylor College of Medicine, fared far better than those treated with phosphate-buffered saline (PBS) or alendronate (ALN) or trastuzumab (Tras) alone 82 days after tumor implantation. Courtesy of Baylor College of Medicine/Rice University

The result is a molecule that seeks out bone tumors and stays put, giving the drug time to kill tumor cells. It helps that bisphosphonate molecules prefer acidic sites like bone tumors, keeping the drug concentration higher there than in surrounding healthy tissue.

The researchers chose breast cancer drugs because while many recover from the disease, 20 to 40% of breast cancer survivors eventually suffer metastases to distant organs, with metastasis to bone occurring in about 70% of these cases, significantly increasing mortality, they said.

While chemotherapy, hormone and radiation therapy used to treat women with bone metastatic breast cancers can shrink or slow bone metastasis, they usually do not eliminate the metastases, Xiao said.

“Bone is kind of a fertile soil for cancer cell,” Xiao said. “If a cancer cell reaches it, then it has a really good chance to grow and to further migrate, for example to the brain, the heart, the liver or to other tissues. That’s a really bad situation for a patient.”

Xiao hopes to get the compound into a clinical trial, and sees potential for custom conjugates that treat other tumors prone to metastasis, including prostate cancer.

Postdoctoral researchers Zeru Tian of Rice and Ling Wu of Baylor are co-lead authors of the paper. Co-authors are graduate students Chenfei Yu, Yuda Chen, Axel Loredo and Kuan-Lin Wu and postdoctoral researcher Lushun Wang of Rice; and postdoctoral fellows Zhan Xu, Igor Bado and Weijie Zhang and instructor Hai Wang of Baylor.

Xiang Zhang, left, at Baylor College of Medicine, and Han Xiao at Rice University have developed an antibody conjugate called BonTarg that delivers drugs to bone tumors and inhibits metastasis. (Credit: Rice University/Baylor College of Medicine)

Xiao is the Norman Hackerman-Welch Young Investigator, the Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research and an assistant professor of chemistry, bioengineering and biosciences. Zhang is the William T. Butler, M.D., Endowed Chair for Distinguished Faculty, McNair Scholar, associate director of the Lester and Sue Smith Breast Center, professor of molecular and cellular biology and member of the Dan L Duncan Comprehensive Cancer Center.

The research was supported by CPRIT, the National Institutes of Health, the Robert A. Welch Foundation, the U.S. Department of Defense, the John S. Dunn Foundation, the Hamill Foundation, the Breast Cancer Research Foundation and the McNair Medical Institute.

Read the abstract at https://advances.sciencemag.org/lookup/doi/10.1126/sciadv.abf2051.


Provided by Rice University

Researchers Discover Gene Linked to Bone Cancer in Children, ID Potential Novel Therapy (Medicine)

Researchers have discovered a gene, OTUD7A, that impacts the development of Ewing sarcoma, a bone cancer that occurs mainly in children. They have also identified a compound that shows potential to block OTUD7A protein activity. The finding, by scientists at the University of North Carolina and the Lineberger Comprehensive Cancer Center, appeared online June 1, 2021, in Advanced Science.

About 250 children and young adults are diagnosed with Ewing sarcoma each year in the U.S. About half of those diagnosed will ultimately succumb to the disease, pointing to the need for better therapies.

“Our primary research focus targeted the EWS-FLI1 fusion protein found in about 85 percent of Ewing sarcoma patients,” said UNC Lineberger’s Pengda Liu, PhD, assistant professor of Biochemistry and Biophysics in the UNC School of Medicine and co-lead author. “This protein, made up of pieces of two other proteins, is unique to Ewing sarcoma and only produced in cancer cells, making it an excellent target for treatment.”

Critical relationships between proteins contribute to the development of cancers such as Ewing sarcoma. So, it was a seminal discovery when the UNC researchers found that OTUD7A controls the cancer-causing fusion protein.

Ian Davis, MD, PhD: “Once the basic science validated our biological approaches, the application of computational virtual screening enabled us to quickly identify a lead molecule for further testing and validation.” © UNC Lineberger Comprehensive Cancer Center

Armed with this knowledge, the scientists went on the hunt for small molecule compounds that could block OTUD7A’s activity. Their collaborator, Atomwise Inc., used an artificial intelligence program known as AtomNet to screen four million small molecules to find ones that could fit into a pocket in OTUD7A. One compound they identified, 7Ai, showed a good ability to reduce tumor formation in mice that were grafted with human Ewing sarcoma cells. The compound did not appear to be toxic and was well-tolerated. Also, 7Ai did not kill normal cells that were tested in lab culture experiments.

“Treatment with 7Ai could provide a new targeted therapeutic option for patients who become resistant to chemotherapy. Developing an effective drug will require more lab work and then clinical studies, however,” said Liu.

“By deeply exploring the key cellular processes that lead to cancer, unexpected potential therapeutic avenues can result,” said co-author Ian Davis, MD, PhD, G. Denman Hammond Professor of Childhood Cancer and co-leader of the Cancer Genetics Program at UNC Lineberger. “Once the basic science validated our biological approaches, the application of computational virtual screening enabled us to quickly identify a lead molecule for further testing and validation.”

The researchers are currently working with the UNC Eshelman School of Pharmacy to improve 7Ai’s potency and specificity.

“I am particularly indebted to a UNC student with metastatic Ewing sarcoma who made it a priority to donate tissue that could be used for research,” said Davis, who is also the associate division chief of pediatric hematology-oncology. “We’re also appreciative of funding for our research through an NIH Beau Biden Pediatric Cancer Moonshot grant, which came about after the cancer-related death of President Biden’s son.”

Authors

In addition to Liu and Davis, the paper’s other authors at UNC include Siyuan Su, PhD, Jianfeng Chen, PhD, Yao Jiang, Ying Wang, PhD, Tamara Vital, Jiaming Zhang, MD, Zhichuan Zhu, PhD, Alex W. Prevatte, Natalie K. Barker, and Laura E. Herring, PhD. Christian Laggner and Kong T. Nguyen are at Atomwise Inc., San Francisco.

Featured image: UNC Lineberger’s Pengda Liu, PhD, and colleagues have discovered a gene, OTUD7A, that impacts the development of Ewing sarcoma, a bone cancer that occurs mainly in children, as well as a compound that shows potential to block OTUD7A protein activity. © UNC Lineberger Comprehensive Cancer Center


Reference: Su, S., Chen, J., Jiang, Y., Wang, Y., Vital, T., Zhang, J., Laggner, C., Nguyen, K. T., Zhu, Z., Prevatte, A. W., Barker, N. K., Herring, L. E., Davis, I. J., Liu, P., SPOP and OTUD7A Control EWS–FLI1 Protein Stability to Govern Ewing Sarcoma Growth. Adv. Sci. 2021, 2004846. https://doi.org/10.1002/advs.202004846


Provided by UNC

Cancer Researchers Identify Potential New Class of Drugs to Treat Blood and Bone Marrow Cancers (Medicine)

A new study by researchers in Cleveland Clinic’s Taussig Cancer Institute and Lerner Research Institute describes a novel class of targeted cancer drugs that may prove effective in treating certain common types of leukemia. The results first appeared online in Blood Cancer Discovery.

Myeloid leukemias are cancers derived from stem and progenitor cells in the bone marrow that give rise to all normal blood cells. One of the most common mutations involved in driving myeloid leukemias are found in the TET2 gene, which has been investigated for the last decade by Jaroslaw Maciejewski, MD, Ph.D., a practicing hematologist and chair of the Cleveland Clinic Department of Translational Hematology & Oncology Research.In the new study, Dr. Maciejewski and his collaborator in the Department of Translational Hematology & Oncology Research, Babal Kant Jha, Ph.D., report a new pharmacological strategy to preferentially target and eliminate leukemia cells with TET2 mutations.

“In preclinical models, we found that a synthetic molecule called TETi76 was able to target and kill the mutant cancer cells both in the early phases of disease—what we call clonal hematopoiesis of indeterminate potential, or CHIP—and in fully developed TET2 mutant myeloid leukemia,” said Dr. Maciejewski.

The research team designed TETi76 to replicate and amplify the effects of a natural molecule called 2HG (2-hydroxyglutarate), which inhibits the enzymatic activity of TET genes.The TET DNA dioxygenase gene family codes for enzymes that remove chemical groups from DNA molecules, which ultimately changes what genes are expressed and can contribute to the development and spread of disease.

While all members of the TET family are dioxygenases, the most powerful enzymatic activity belongs to TET2. Even when TET2 is mutated, however, its related genes TET1 and TET3 provide residual enzymatic activity. While significantly less, this activity is still enough to facilitate the spread of mutated cancer cells. Drs. Maciejewski’s and Jha’s new pharmacologic strategy to selectively eliminate TET2 mutant leukemia cells centers on targeting their reliance on this residual DNA dioxygenase activity.”We took lessons from the natural biological capabilities of 2HG,” explained Dr. Jha, a principal investigator.. “We studied the molecule and rationally designed a novel small molecule, synthesized by our chemistry group headed by James Phillips, Ph.D. Together, we generated TETi76—a similar, but more potent version capable of inhibiting not just TET2, but also the remaining disease-driving enzymatic activity of TET1 and TET3.”

The researchers studied TETi76’s effects in both preclinical disease and xenograft models (where human cancer cells are implanted into preclinical models). Additional studies will be critical to investigate the small molecule’s cancer-fighting capabilities in patients.”We are optimistic about our results, which show not just that TETi76 preferentially restricts the growth and spread of cells with TET2 mutations, but also gives survival advantage to normal stem and progenitor cells,” said Dr. Jha.

Myeloid leukiemias are commonly treated with chemotherapy, either alone or in combination with targeted drugs. More research is needed, but this early preclinical data suggest TETi76 may be a promising, more effective candidate to replace the targeted drugs currently used.

References: Yihong Guan et al, A Therapeutic Strategy for Preferential Targeting of TET2 Mutant and TET-dioxygenase Deficient Cells in Myeloid Neoplasms, Blood Cancer Discovery (2020). DOI: 10.1158/2643-3230.BCD-20-0173

Provided by Cleveland Clinic

Bioactive Glass As a New Approach In The Treatment of Bone Cancer (Oncology / Medicine)

FAU develops bioactive glass for bone cancer research.

A team of researchers at FAU led by Prof. Dr. Aldo R. Boccaccini, Chair of Materials Science (Biomaterials) is producing bioactive glass that is being tested for suitability in the treatment of giant-cell tumours of the bone at Heidelberg University Hospital as part of a cooperation project. The cancer research foundation Deutsche Krebshilfe is funding the project with approximately 212,000 euros.

Prof. Dr. Aldo R. Boccaccini (Chair of Materials Science – Biomaterials) (Image: FAU)

The tiny particles of glass that contain biologically active ions such as zinc, magnesium or boron are being examined to determine if they form carbonated hydroxyapatite (CHA) upon contact with bodily fluids. The formation of such a layer of CHA enables the particles of glass to interact with the bone tissue. The team led by Prof. Dr. Aldo R. Boccaccini is one of the world’s leading groups researching into the development, production and characterisation of bioactive glass.

In the treatment of broken bones, patients are already benefiting from the effects of bioactive glass, which stimulate bone growth. However, these types of glass can also have a destructive effect on cells and this is exactly what the researchers at Heidelberg University Hospital hope to make use of. Cancer cells from giant-cell tumours of the bone seem to react more sensitively than healthy bone cells. The aim is to selectively kill off cancer cells thus preventing local relapses or recurring tumours. Relapses occur relatively frequently in giant-cell tumours and can lead to a serious form of the disease. The researchers hope to improve treatments for cancer patients with the glass.

Provided by Friedrich-Alexander-Universität Erlangen-Nürnberg