Okayama University


Okayama University Medical Research Updates (OU-MRU)Vol.93

August 03, 2021

Source: Okayama University (JAPAN), Public Relations Division
For immediate release: 3 August 2021
Okayama University research: Repurposing cancer drugs: An innovative therapeutic strategy to fight bone cancer.

(Okayama, 3 August) In a study reported in the journal Molecular Cancer Therapeutics, researchers from Okayama University describe the effects of pexidartinib, a drug targeting macrophages infiltrating into a tumor, for bone and soft-tissue malignancies.

Sarcoma is a rare form of cancer that often originates within bones and then spreads to other organs. A distinct feature of cancer and sarcoma is the presence of tumor-associated macrophages (TAMs). These are usually healthy blood cells which have been converted by cancer cells to turn against the body and help their perpetrators spread. Now, in a collaboration between Okayama University and the Memorial Sloan Kettering Cancer Center, a research team has shown that PLX3397 (pexidartinib), a drug that can inhibit the formation of TAMs, is effective in mitigating the spread of sarcoma.

Colony stimulating factor 1 (CSF-1) is a cytokine secreted by cancer cells which oversees the creation of TAMs. PLX3397 is known to effectively inhibit CSF-1/CSF-1 receptor (CSF-1R) on TAMs. Now, in this study the researchers investigated whether this ability of PLX3397 could be leveraged in sarcoma too.

Sarcoma cells were first analyzed to confirm that they secreted CSF-1. Next, blood cells were extracted from mice and grown in the same environment as these sarcoma cells. Subsequently, the blood cells started proliferating faster and showing TAM-like tendencies. When the genetic makeup of these nascent TAMs was assessed, the team found showed that they had transformed into M2-like macrophages, a subtype that indeed promotes tumor growth. The mixture of cells was then treated with varying doses of PLX3397 to find that the drug curbed the transformation, growth, and movement of TAMs.

Next, the effects of PLX3397 in a mouse model of bone cancer were examined. Sarcoma cells were transplanted into the tibial bones of mice and monitored for a few weeks. By the end of 3 weeks, the cancer had grown and spread into the lungs of these mice. However, mice who had been treated with high doses of PLX3397 not only showed smaller tumors within their bones, but also displayed no signs of cancer within their lungs. Lastly, the team extracted tumor tissues from these mice to study the cancer cells closely. It was found that PLX3397 also increased the presence of cancer-fighting immune cells, CD8 T cells, within these tumors. PLX3397 thus showed an effective inhibition of sarcoma in cellular and animal models.

“Our preclinical results show that PLX3397 has strong macrophage- and T cell-modulating effects that may translate into cancer immunotherapy for bone and soft tissue sarcomas,” conclude the researchers. Although successful results still need to be shown in human clinical trials, this study paves the way for an effective new way to tackle sarcoma.

Sarcoma: Sarcoma is a form of cancer that originates within bone tissue or soft tissues such as the muscles, fat, or tendons. The former type, osteosarcoma, is the most common subtype of bone cancer and affects mostly teens and young adults. Sarcomas have a high potential of spread to distant organs, predominantly to the lungs.

At present, nearly a third of patients respond very poorly to the available therapies for sarcoma. Thus, development of targeted therapies and/or immunotherapies for bone and soft-tissue sarcomas is crucial.

Tumor-associated macrophages (TAMs): In certain forms of cancer, innocuous blood cells are recruited by cancerous ones and converted into specialized immune cells called TAMs. Under usual circumstances, macrophages help the body ward off invaders and combat infection (M1-like macrophages). However, the CSF-1 secreted by cancer cells within the tumor milieu generates macrophages which promote the growth and progression of tumors (M2-like macrophages). Owing to this property, inhibition of CSF-1/CSF-1R is being investigated as a therapeutic target against TAMs in the different cancerous tissues.

Tomohiro Fujiwara, Mohamed A. Yakoub, Andrew Chandler, Alexander B. Christ, Guangli Yang, Ouathek Ouerfelli, Vinagolu K. Rajasekhar, Aki Yoshida, Hiroya Kondo, Toshiaki Hata, Hiroshi Tazawa, Yildirim Dogan, Malcom A.S. Moore, Toshiyoshi Fujiwara, Toshifumi Ozaki, Ed Purdue, John H. Healey. CSF-1/CSF-1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-Cell Infiltration in the Sarcoma Microenvironment. Molecular Cancer Therapeutics, 2021 Jun 4;molcanther.0591.2020.
DOI: 10.1158/1535-7163.MCT-20-0591
CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-cell Infiltration in the Sarcoma Microenvironment | Molecular Cancer Therapeutics

Correspondence to
Assistant Professor FUJIWARA Tomohiro, M.D.,Ph.D.
Department of Orthopaedic Surgery,
Graduate School of Medicine, Dentistry and Pharmaceutical Science,
Okayama University, 2-5-1 Shikata-cho, Kita-ku,
Okayama 700-8558, Japan
E-mail: tomomedvn(a)okayama-u.ac.jp
For inquiries, please contact us by replacing (a) with the @ mark.

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The whole volume : OU-MRU (1- )
Vol.1:Innovative non-invasive ‘liquid biopsy’ method to capture circulating tumor cells from blood samples for genetic testing
Vol.2:Ensuring a cool recovery from cardiac arrest
Vol.3:Organ regeneration research leaps forward
Vol.4:Cardiac mechanosensitive integrator
Vol.5:Cell injections get to the heart of congenital defects
Vol.6:Fourth key molecule identified in bone development
Vol.7:Anticancer virus solution provides an alternative to surgery
Vol.8:Light-responsive dye stimulates sight in genetically blind patients
Vol.9:Diabetes drug helps towards immunity against cancer
Vol.10:Enzyme-inhibitors treat drug-resistant epilepsy
Vol.11:Compound-protein combination shows promise for arthritis treatment
Vol.12:Molecular features of the circadian clock system in fruit flies
Vol.13:Peptide directs artificial tissue growth
Vol.14:Simplified boron compound may treat brain tumours
Vol.15:Metamaterial absorbers for infrared inspection technologies
Vol.16:Epigenetics research traces how crickets restore lost limbs
Vol.17:Cell research shows pathway for suppressing hepatitis B virus
Vol.18:Therapeutic protein targets liver disease
Vol.19:Study links signalling protein to osteoarthritis
Vol.20:Lack of enzyme promotes fatty liver disease in thin patients
Vol.21:Combined gene transduction and light therapy targets gastric cancer
Vol.22:Medical supportive device for hemodialysis catheter puncture
Vol.23:Development of low cost oral inactivated vaccines for dysentery
Vol.24:Sticky molecules to tackle obesity and diabetes
Vol.25:Self-administered aroma foot massage may reduce symptoms of anxiety
Vol.26:Protein for preventing heart failure
Vol.27:Keeping cells in shape to fight sepsis
Vol.28:Viral-based therapy for bone cancer
Vol.29:Photoreactive compound allows protein synthesis control with light
Vol.30:Cancer stem cells’ role in tumor growth revealed
Vol.31:Prevention of RNA virus replication
Vol.32:Enzyme target for slowing bladder cancer invasion
Vol.33:Attacking tumors from the inside
Vol.34:Novel mouse model for studying pancreatic cancer
Vol.35:Potential cause of Lafora disease revealed
Vol.36:Overloading of protein localization triggers cellular defects
Vol.37:Protein dosage compensation mechanism unravelled
Vol.38:Bioengineered tooth restoration in a large mammal
Vol.39:Successful test of retinal prosthesis implanted in rats
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Vol.41:Inorganic biomaterials for soft-tissue adhesion
Vol.42:Potential drug for treating chronic pain with few side effects
Vol.43:Potential origin of cancer-associated cells revealed
Vol.44:Protection from plant extracts
Vol.45:Link between biological-clock disturbance and brain dysfunction uncovered
Vol.46:New method for suppressing lung cancer oncogene
Vol.47:Candidate genes for eye misalignment identified
Vol.48:Nanotechnology-based approach to cancer virotherapy
Vol.49:Cell membrane as material for bone formation
Vol.50:Iron removal as a potential cancer therapy
Vol.51:Potential of 3D nanoenvironments for experimental cancer
Vol.52:A protein found on the surface of cells plays an integral role in tumor growth and sustenance
Vol.53:Successful implantation and testing of retinal prosthesis in monkey eyes with retinal degeneration
Vol.54:Measuring ion concentration in solutions for clinical and environmental research
Vol.55:Diabetic kidney disease: new biomarkers improve the prediction of the renal prognosis
Vol.56:New device for assisting accurate hemodialysis catheter placement
Vol.57:Possible link between excess chewing muscle activity and dental disease
Vol.58:Insights into mechanisms governing the resistance to the anti-cancer medication cetuximab
Vol.59:Role of commensal flora in periodontal immune response investigated
Vol.60:Role of commensal microbiota in bone remodeling
Vol.61:Mechanical stress affects normal bone development
Vol.62:3D tissue model offers insights into treating pancreatic cancer
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Vol.65:Game changer: How do bacteria play Tag ?
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Vol.67:Technology to rapidly detect cancer markers for cancer diagnosis
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Vol.73:Primary intraocular lymphoma does not always spread to the central nervous system
Vol.74:Rising from the ashes—dead brain cells can be regenerated after traumatic injury
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Vol.78:Disrupting blood supply to tumors as a new strategy to treat oral cancer
Vol.79:Novel blood-based markers to detect Alzheimer’s disease
Vol.80:A novel 3D cell culture model sheds light on the mechanisms driving fibrosis in pancreatic cancer
Vol.81:Innovative method for determining carcinogenicity of chemicals using iPS cells
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