Finding novel therapies for childhood cancer

Since the first time she treated a child with neuroblastoma, Giselle Saulnier Sholler wanted to do the impossible for her patients. Neuroblastoma is the most common extracranial solid tumor in children with roughly 700 new diagnoses every year. The survival rate is 30% and for patients who relapse following conventional standard of care treatments, the survival rate is less than 10%.

“The outcomes are really poor,” said Sholler, director of pediatric oncology research at Penn State College of Medicine and division chief of pediatric hematology and oncology at Penn State Health Children’s Hospital. “It breaks my heart. These are young parents with young kids. I couldn’t keep doing the same thing over and over again, only to see the same results.”

Sholler set out to find novel therapies and create the results she wanted to see. In December 2023, the Food and Drug Administration (FDA) approved eflornithine (DFMO), the first drug to reduce the risk of relapse and increase survival in high-risk pediatric neuroblastoma patients, the culmination of 20 years of Sholler’s research, clinical trials and patient care.

With her work, Sholler has helped make Penn State College of Medicine and Penn State Health a destination for pediatric cancer patients from all over the world. Recently, Penn State News caught up with Sholler to learn more about her quest to transform cancer care.

You’re a clinician-scientist. How does your clinical practice inform your research priorities and vice versa?

It’s circular: What we learn from patients, we bring to the lab and what we learn in the lab, we bring back to patients. It’s critical for finding new therapies for kids with cancer and for understanding cancer better.

In 2019, I started looking at the genomic sequencing of tumors because I wanted to understand why, for example, 30% of patients responded to a drug but the rest don’t even though they have the same cancer. What mutations are in this particular child’s tumor? What are the pathways that are making this specific tumor grow?

In my lab, we grow the cell lines from patients’ tumors and test different currently available drugs to see what works. Will it respond, or do we need to develop new drugs? For instance, we found a new mutation in one child. Had we not grown that cell line, we would never have known what this mutation does or how to treat it.

It’s led to two lanes of research—one testing drugs in clinical trials that could target these pathways and one pursuing a precision medicine approach that uses genomic information from a patient’s tumor to create treatment plans tailored to the patient.

This approach has led to innovations in molecular guided therapy, which uses genetic information from a patient’s tumor to guide treatment decisions. Can you talk about that?

Since September, when I came to Penn State, we have initiated a program wherein every child with cancer has genomic sequencing. Every child that needs it—not just the hardest-to-treat patients—has a molecular tumor board, which is a panel of experts who review the patient’s clinical and genomic profile and matches them with personalized treatment plans. The earlier we can do this, the earlier we can identify the combination of drugs that is right for that patient.

Tumors are smart. If you block one pathway, they find another way to continue growing. To make the biggest difference for patients, it is important to combine drugs and target the different pathways to result in tumor cell death. For example, we have brain tumor cells from one patient in my lab. When we treated the tumor cells with drugs individually, they had very little effect. When we combined the same drugs together, they killed the tumor.

Recently, you published a paper about a recent trial where you combined DNA and RNA profiling of tumor samples with a molecular tumor board to make real-time treatment decisions for children with cancer. What was unique about this study?

Typically, molecular-guided treatment is based on DNA analysis of the tumor. If you have mutation X, you get drug X. In adults, mutations happen because the DNA of mature cells have been damaged by environmental factors like sun, smoke and toxins, which can lead to cancer.

But in pediatric cancer, there are far fewer mutations and they are not caused by environmental toxins. Mistakes happen while the body develops, which can cause cancer. Neuroblastoma or brain tumors typically develop up to five or six years of age because that’s when the nervous system develops.

We conducted the first patient trial where combinations of drugs—all FDA-approved drugs with standard dosing and pharmacist oversight—were recommended by a molecular tumor board and incorporated RNA analysis with DNA analysis. RNA analysis allowed us to look at pathways in the body, which may be normal but may be over-expressed, driving tumor development.

We had 144 patients participate. These patients had relapsed central nervous system, neuroblastoma, sarcomas and other rare solid tumors, were not responding to standard therapies and were incurable. Sixty-five percent showed clinical benefit. In the majority, tumor size decreased.

If we’re not looking at the RNA, we wouldn’t have had the same outcomes. Eighty percent of the molecular tumor board decisions were made based on RNA analysis versus only 20% based on DNA analysis.

In December 2023, the FDA approved DFMO. When you finally got word of approval, what was your reaction? How is the roll-out going?

Incredible relief and gratitude. I was expecting it, but I couldn’t believe it truly happened. For so long, we were told it was never going to happen; that the FDA would not approve a drug based on a single-arm study without a randomized placebo-controlled trial.

I’m so thankful for all the families who now have access to it. Previously, a patient needed to be at one of our hospitals or afford to travel to access DFMO through a trial. Now, physicians across the country are prescribing it.

You’re also learning more about how DFMO works. In a research paper earlier this year, findings from your team suggests that DFMO inhibits cellular processes in neuroblastoma cells that are integral to tumor formation. Why is this important?

So many drugs are cytotoxic; they kill cancer cells. But DFMO doesn’t work this way and understanding how the drug works helps us better understand when and how to use it in treatment. We look at the mechanism so that we can also understand what other drugs we could combine to make it even more effective. With DFMO, we’ve reduced the relapse rate from 40% to 15%, but until we get to zero, we haven’t finished our job.

Can you talk about some of the upcoming clinical trials you have planned?

We submitted a trial to the FDA for approval to use tipifarnib combined with naxitamab in neuroblastoma patients, based on the work of H.G. Wang, Lois High Berstler Professor of Pediatrics and of Pharmacology at Penn State College of Medicine, and received the approval to move forward with this study. Naxitamab is an antibody therapy specific for neuroblastoma and tipifarnib improves the immune system response to increase the effectiveness of the antibody.

We’ve also written a clinical trial targeting CK2, an enzyme that controls many cellular processes, based on the work of Chandrika Behura, associate professor at Penn State College of Medicine and under review at the FDA. We expect both of those trials to be open by the fall.

We’re expanding our work on DFMO in neuroblastoma to include a drug called AMXT. We found that the two drugs together starved the neuroblastoma cells, resulting in greater inhibition of tumor formation. This combination will be tested in children with neuroblastoma as well as DIPG, a type of brain tumor found in the brainstem. They’re doing well on DFMO. Can they do better if we add AMXT? We have FDA approval, and the study will open shortly.

We’re also expanding our trials to other indications like sarcomas and DIPG, which is a brain tumor found in the brainstem and the only pediatric cancer that’s 100% fatal.

Parents, advocates and philanthropists have played a huge role in your career. Why is that important?

My whole career has been a partnership with patients, parents and advocates. They’ve been instrumental. They formed the Beat Childhood Cancer Foundation to raise money to support the research conducted by the group we founded and lead at Penn State—the Beat Childhood Cancer Research Consortium, an international group of 50-plus universities and children’s hospitals. Now, we have Four Diamonds supporting our work here at Penn State.

Philanthropy drives pediatric cancer because, unfortunately, there’s little money from the government and it’s not a smart investment for pharmaceutical companies. There are only 700 kids with neuroblastoma across the United States and among those, only about 400 high-risk patients who need treatment. It’s really left to the families to help raise money so we can do this research.

What’s next?

The other areas we’re really interested in are immunotherapy and cellular therapy. We know that patients make an immune response against their cancer but it’s never big enough to make the tumor regress. What we’re doing is taking a patient’s tumor cell and their white cells, the cells that cause an immune response, and creating a personalized vaccine. When we give this to patients, it activates their T cells against their own cancer. We can then harvest those T cells, grow them in the lab, and then infuse them back to the patient so that their immune system can mount an attack against the cancer. We opened a study here for neuroblastoma and DIPG in April and have enrolled our first patient.