Dr. Yael P. Mossé Leads International Study to Degrade MYCN Protein in Pediatric Cancers

Sep 01, 2021

Study Builds on Research Supported by Conquer Cancer

By Jimmy O’Hara, Conquer Cancer

When cancer-causing genes like anaplastic lymphoma kinase (ALK) are successfully targeted, they essentially shut off. Yael P. Mossé, MD, of The Children’s Hospital of Philadelphia (CHOP), made this discovery in 2008 with funding support from Conquer Cancer, the ASCO Foundation. This knowledge is the foundation of the life-changing treatment she has been providing to children and adults with neuroblastoma. Her breakthrough led to the drug now known as crizotinib, used to treat a subset of patients with neuroblastoma. Her discovery also helps a population of children and adolescents living with rare tumors that activate the ALK gene, such as anaplastic large-cell lymphoma (ALCL) and inflammatory myofibroblastic tumors (IMT). 
“These patients [experienced] robust and durable complete antitumor responses in cases with proven ALK rearrangements,” said Dr. Mossé. “This led to crizotinib’s FDA breakthrough designation in May 2018 in the context of relapsed ALCL and official FDA approval for children and adolescents with relapsed/refractory ALCL in January 2021.”
However, patients whose neuroblastoma has different or additional genetic alterations, like N-myc proto-oncogene protein (MYCN), are unlikely to have a response to crizotinib. So, Dr. Mossé continues her relentless work to conquer cancer. 

Uncovering a Culprit 

Nearly 20 years since receiving a Conquer Cancer Young Investigator Award (YIA) and Career Development Award (CDA), Dr. Mossé is launching a new study to unmask how the MYCN culprit causes certain diseases to develop resistance to existing cancer drugs. 
“Much of my research focus is on establishing ALK as a molecular target across diverse pediatric and adult tumors,” said Dr. Mossé. “If the science and early phase clinical trial are both correct, we will see a significant improvement in cure rates for patients with high-risk neuroblastoma whose tumors harbor an ALK alteration.”
Dr. Mossé is testing the efficacy of lorlatinib, an emerging cancer drug designed to treat patients whose genes express stubborn alterations like MYCN, as well as canonical ALK mutations that do not respond to crizotinib. While some parts of their tumor(s) respond to treatment, other regions continue to expand. These intra-patient differences are challenging cancer researchers.
“We are seeing the emergence of resistance to lorlatinib in our phase I study. This is unsurprising as many of these patients have highly heterogeneous disease, such that some cells have an addiction to the ALK gene and others do not and have been exposed to earlier generations of ALK inhibitors,” said Dr. Mossé. 
“The MYCN family of oncogenic proteins has to date been considered undruggable because they are intrinsically disordered,” said Dr. Mossé. “Structured regions amenable to direct therapeutic inhibition have yet to be identified. We have put together a team of world experts to solve this problem and this effort is being funded by Alex’s Lemonade Stand Foundation.”

Transatlantic Teamwork 

With an integrated, international phase III project between the Children’s Oncology Group (COG) and the SIOPEN Association, a European organization involved in neuroblastoma research, Dr. Mossé and her team will use liquid biopsies to help identify mechanisms of resistance to targeted therapy. Results will be used in the lab to model resistance, informing the creation of dual targeting strategies. “This should result in a landmark step in clinical research for children with neuroblastoma, representing the first ever COG and SIOPEN joint initiative,” said Dr. Mossé. 
“Eventually, we intend to discover and develop drugs that will directly degrade the MYCN protein in some of the most important pediatric cancers, including neuroblastoma, medulloblastoma, and rhabdoid tumors.” 

A Legacy of Research Mentorship 

John M. Maris, MD, of CHOP, was a mentor to Dr. Mossé during her fellowship. Dr. Mossé credits Dr. Maris, a fellow Conquer Cancer YIA and CDA alum, for encouraging her to apply for Conquer Cancer funding. Medicine isn’t Dr. Maris’ and Dr. Mossé’s only collaboration; the colleagues are now married.
The Maris-Mossé mentorship now supports another promising researcher. Dr. Mossé’s mentee, Esther Berko, MD, PhD, a pediatric oncology fellow, received a 2021 Conquer Cancer YIA.
“Dr. Mossé has been an incredible mentor to me,” said Dr. Berko. “Not only is she an outstanding researcher, but as a YIA recipient herself, she truly understands the role of a mentor in fostering and encouraging trainees to develop as independent researchers and providing the opportunities and support to do so.” 
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