Dr. Andrei Thomas-Tikhonenko – The Children’s Hospital of Philadelphia


Children’s Hospital of Philadelphia

in collaboration with University of Pennsylvania and Johns Hopkins University

CureSearch Acceleration Initiative Award: 2022-2025 

Focus: High-Risk Pediatric Cancers – Neuroblastoma and Diffuse Midline Glioma

Project title: Targeting splicing-derived neo-epitopes in high-risk pediatric cancers

For this work, Dr. Andrei Thomas-Tikhonenko chose two malignancies, based on the existence of validated targets, the availability of high-quality RNA-Seq data and primary samples, strong expertise of collaborators, and – last but not least – urgent and unmet clinical need: 

Neuroblastoma: Children diagnosed with neuroblastoma are typically younger than 5 years old. Most high-risk neuroblastoma patients die despite intensive cytotoxic therapies, and survivors are burdened with treatment-related long-term effects. A child diagnosed with neuroblastoma today is subjected to a highly intensive regimen of toxic chemotherapeutics, radiation therapy, and an immunotherapy that, while effective, is toxic, with pain and anaphylaxis commonly leading to drug discontinuation. Return of the disease still occur sin at least half of the treated patients. 

Diffuse Midline Glioma: Pediatric brain tumors are a leading cause of cancer death in children in the U.S. and diffuse midline glioma (DMG) is one of the most defiant to traditional therapies and these tumors can also be impossible to surgically remove. Currently, there are no effective standard of care therapies for DMG, despite decades of clinical trials. Children affected by DMG nearly universally succumb to the disease within 8-10 months of diagnosis. 

Andrei Thomas-Tikhonenko, PhD, is a CureSearch Acceleration Initiative Awardee conducting research at the Children’s Hospital of Philadelphia. Pediatric cancers, both hematologic and solid, typically have low mutation burden. This could make them invisible to the immune system which is trained to recognize foreign molecules. Therefore, immune checkpoint inhibitors, which have revolutionized cancer treatments in adults, have gained virtually no traction in the realm of childhood malignancies. Antibody-based immunotherapies like CAR T-cell therapy use markers on the surface of cancer cells that differentiate them from normal cells as targets for the immune system. Determining markers that are different from normal cells is essential so that the therapy is tumor-specific and does not damage normal cells. In many tumors, because they are derived from our own cells, it can be hard to find such markers. Dr. Thomas-Tikhonenko and his colleagues will identify novel immunotherapy targets resulting from a process called aberrant splicing. This process results in protein variants that are not found in normal cells. Because these altered cell surface proteins are not found on normal cells, they are an excellent, specific target for immunotherapy. Therapeutics that are developed during this project to recognize these cancer-specific cell-surface proteins will be able to either direct the immune system to destroy cancer cells or deliver therapeutics to the tumor while minimizing damage to normal cells resulting in fewer instances of dose-limiting toxicity and more effective therapy. 

Research Update April 2024:

The overarching goal of Dr. Thomas-Tikhonenko's project is to identify new, more specific targets for immunotherapy for two deadly pediatric cancers: diffuse midline glioma (DMG) and neuroblastoma (NB). Both cancers originate in the nervous system, with DMG located in the brain and being universally fatal.  

Their goal is to identify not just proteins overproduced by tumors, but rather tumor-specific cell surface protein variants. Informed by their previous work, Dr. Thomas-Tikonenko and his team have decided to exploit a unique property of some proteins to either include or skip so-called microdomains, very short strings of amino acids dynamically regulated in the developing nervous system. They have found that such proteins are extremely prevalent in DMG, one prominent example being the cell adhesion molecule NRCAM. In fact, in the past twelve months the team has demonstrated that one of the DMG-specific NRCAM variants makes DMG more invasive. Their more recent work resulted in the identification of several antibodies capable of distinguishing between the normal and the DMG-specific NRCAM variants. Similar findings were made using as a model NB samples. 

Dr. Thomas-Tikhonenko's latest research advance is the identification of the protein P2RX3 as a highly specific marker of NB, which is not expressed in the vast majority of normal organs. Targeting of tumor-specific isoforms of NRCAM and P2RX3 could represent the future of immunotherapy, capable of killing tumor cells while sparing surrounding tissues. 


“We have been working for several years to determine whether messenger RNAs pervasively mis-spliced in cancer cells give rise to aberrant protein isoforms, and whether these isoforms can be found on cell surface and targeted with a new generation of immunotherapeutics. Just last year we generated a first-in-class antibody specific for the mis-spliced CD22 surface marker commonly found in B-lymphoblastic leukemia. Now we aspire to extend this target discovery pipeline to some of the deadliest pediatric cancers: high-grade gliomas and neuroblastomas. They originate, respectively, in the central and peripheral nervous systems and share most surface markers with normal neurons. This makes the development of immunotherapeutic challenging, but we hope that our novel strategy will overcome traditional obstacles.” 

-Dr. Andrei Thomas-Tikhonenko

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