Posted July 13, 2022

As the most common type of bone cancer in the pediatric, adolescents, and young adults (PAYA) population, osteosarcoma (OS) accounts for approximately 2% of malignancies in the PAYA population; approximately 500 children and teenagers are diagnosed with OS each year.¹ The demographics of OS show it occurs more in males, and is slightly more common in African Americans and Hispanics compared to Caucasians. The current 5-year survival rate for PAYA OS remains at 60%, the same survival rate for the last 30 years.¹ Due to its genetic complexity, OS continues to be a disease with very few druggable mutations – changes in a gene and gene product that may be easily treated with an intervention, such as chemotherapy or immunotherapy.

New treatments are urgently needed to improve prognosis for PAYA OS. One approach focuses on deregulated cellular processes rather than the traditional targeted mutated proteins. A common feature of OS is the impairment of the DNA damage response (DDR), where normal cells identify and correct damage to DNA. If the DNA damage is too severe, the cell will initiate cell death processes (apoptosis).² Impairment of DDR is one of the many ways a cell can become malignant. With Fiscal Year 2021 Impact Awards, Dr. Pollok and Dr. George will target different aspects of DDR as treatment strategies for PAYA OS.

Targeting Replication Stress in Pediatric and AYA Osteosarcoma
Karen Pollok, Ph.D.
Indiana University-Bloomington
Impact Award

The genetic instabilities of OS result in increased copies of genes, called copy number variations (CNVs) that promote increased proliferation, survival, and metastasis. In previous work, Dr. Pollok and her team identified CNVs in genes that regulate cellular processes called DNA replication stress (RS).³ The RS process, unique to cancer cells, promotes genetic instability, such as CNVs, and tumorigenesis due to defective repair of DNA damage. Counterintuitively, enhancing RS induces so much damage it promotes cell death.⁴ Dr. Pollock plans to exploit this strategy to treat OS. By inhibiting two modulators of RS, CHK1 and BETs, Dr. Pollock and her team aim to exacerbate RS and promote OS cell death. The first step dissects the molecular mechanisms into how BETs and CHK1 block OS cell growth and increase cell death. For the second step, a panel of PAYA metastatic OS derived cells representing a range of ages, genders, and ethnicities have been established as pre-clinical models to test BET and CHK inhibitors in combination with conventional chemotherapy as a treatment of metastatic OS. The outcomes of this project will be used to support the development of a precision genomics based clinical trial for PAYA OS patients.

Treatment Options for Metastatic Osteosarcoma
Rani George, M.D., Ph.D.
Dana-Farber Cancer Institute
Impact Award

In recent work, Dr. George and collaborators identified Cyclin-Dependent Kinase 12 (CDK12) gene as a specific therapeutic vulnerability in metastatic OS.⁵ One role of CDK12 involves transcriptional regulation of DDR genes. Since OS cells depend on DNA damage for survival, inhibition of CDK12 creates an overload of genetic instability, thus inducing cellular apoptosis. Dr. George first plans to use clinically relevant models of metastatic OS to demonstrate the efficacy of CDK12 inhibition. To inhibit CDK12, Dr. George’s strategy includes combinational compounds to target the defective DDR response as well as standard chemotherapeutic drugs known to cause DNA damage. In addition, Dr. George and team aim to discover if a commonly overexpressed transcription factor in OS, MYC, plays a role in CDK12 inhibition. Lastly, OS patient samples will be analyzed for MYC levels to estimate the percentage of patients likely to respond to CKD12 inhibitors. The results of this project will inform the initiation of a phase 1 clinical trial for patients with metastatic OS.

References:

¹ https://www.cancer.org/cancer/osteosarcoma/about/what-is-osteosarcoma.html

² Carusillo A and Mussolino C. 2020. DNA damage: From threat to treatment. Cells 9(7):1665. 10 Jul. 2020, doi:10.3390/cells9071665

³ Pandya PH, Cheng L, Saadatzadeh MR, et al. 2020. Systems biology approach identifies prognostic signatures of poor overall survival and guides the prioritization of novel BET-CHK1 combination therapy for osteosarcoma. Cancers 12(9):2426. 26 Aug. 2020, doi:10.3390/cancers12092426

⁴ Zhang J, Dai Q, Park D, and Deng X. 2019. Targeting DNA replication stress for cancer therapy. Genes 7(8):51. 19 Aug. 2016, doi:10.3390/genes7080051

⁵ Bayles I, Krajewska M, Pontius WD, et al. 2019. Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma. The Journal of Clinical Investigation 129(10):4377-4392. doi:10.1172/JCI127718

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Last updated Wednesday, July 13, 2022