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Dr. Matthew Ingham on Personalizing Treatments for Patients With Metastatic Uterine Leiomyosarcoma

Jul 20, 2023

By Jimmy O’Hara, Conquer Cancer 
Accounting for less than 1% of cancer diagnoses each year and between 10% to 20% of sarcomas overall, leiomyosarcomas are both aggressive and highly recurrent—with patients facing a 50% rate of recurrence and, for metastatic disease, an average survival of just 12 to 18 months. While this aggressive tumor can occur in anyone, it’s most likely to affect the uterus, making it most common among women and people with female reproductive organs. 
While managing metastatic and relapsed uterine leiomyosarcoma is possible, it’s also currently incurable with few treatment options—a problem exacerbated by its rarity and the comparative lack of research about the disease, compared to more common metastatic cancers. Consequently, patients with metastatic uterine leiomyosarcoma are still primarily treated with standard chemotherapy. Through his research, Matthew Ingham, MD, of Columbia University, hopes to better understand the biology of this rare disease and expand treatment options for patients with leiomyosarcoma. 
“Rare cancers like sarcoma are often understudied because there is less interest and fewer resources available to support research in this setting,” said Dr. Ingham. “There have been very few advances in the treatment of this disease within the past several decades, and there is no approved effective targeted or immunotherapy-based treatment option.” 
The lack of treatment options, Dr. Ingham explained, is what motivated his research. “We are increasingly recognizing that leiomyosarcoma arising from different anatomic sites may be biologically distinct,” he said, “hence there is value in studying new treatment approaches, specifically within leiomyosarcoma of the uterus.” 
That’s exactly what he’s been doing with the 2019 Career Development Award (CDA) he received from Conquer Cancer, the ASCO Foundation. Through this award, Dr. Ingham launched a National Cancer Institute (NCI)-sponsored, four-step clinical research project to investigate a promising treatment approach for patients with advanced uterine leiomyosarcoma.  

Step One: Reviewing Existing Research 

Before conducting the clinical trial, Dr. Ingham and his team drew from preliminary research to select drugs for evaluation. Emerging research from the Columbia group and others found that uterine leiomyosarcoma may have defects in homologous recombination (HR), a key process for DNA damage and repair. When cancer cells are HR defective, they can accumulate DNA damage which may allow them to behave more aggressively, but also impart a vulnerability to PARP inhibitors, which exacerbate the DNA damage to indefensible levels, resulting in selective cell death in the HR-deficient cancer cells. 
Through this initial work, Dr. Ingham and his mentor, Dr. Gary Schwartz, uncovered two treatments that, when paired together, were highly effective at hindering uterine leiomyosarcoma growth in laboratory models. 
“Olaparib, a targeted therapy, has proven effective in other cancers with these HR defects,” said Dr. Ingham. “These earlier studies identified significant activity for olaparib in combination with low doses of temozolomide, a traditional chemotherapy agent. The low dose of temozolomide appears to potentiate (increase) the activity of olaparib and they work much better than either drug alone.” 

Step Two: Clinical Trial Success 

In Dr. Ingham’s multi-center clinical trial, patients with advanced uterine leiomyosarcoma were treated with olaparib and low-dose temozolomide. The study showed promising results compared to standard treatment options, which are relatively ineffective. Response rates for existing agents hover around 10%, and the sarcoma is kept at bay for only 3 to 4 months before progressing again. Dr. Ingham’s clinical study had a 27% response rate and progression-free survival doubled to nearly 7 months. For the patients who experienced an objective response, the average duration of the response was 12 months. 
This milestone is especially important because the patients enrolled in this trial had already exhausted most treatments available for metastatic leiomyosarcoma. 
“It was very rewarding to see the novel therapy work in such a durable way for these patients who had limited, or no alternatives, and to know that the treatment has extended their lives in a meaningful way and will hopefully continue to do so,” said Dr. Ingham. “Three patients, who had progression of their disease on standard chemotherapy, still remain on the treatment after more than 30 months.” 

Step Three: Better Understanding Tumor Biology 

Beyond showing encouraging results for the new combination therapy, Dr. Ingham and his team used CDA support to collect tumor material before and after treatment. They compared biopsy samples to better understand the biology of uterine leiomyosarcoma, determine why the combination therapy was successful, and help develop a test for identifying which patients are most likely to benefit from this treatment approach. 
“We found that about 35% of patients had defects in genes involved in the homologous recombination DNA repair pathway. This research provided further evidence that uterine leiomyosarcoma has a deficiency in HR. Previously, this was only shown in retrospective studies,” said Dr. Ingham. “These gene alterations might be the reason that the new treatment approach is very effective for some patients.” 

Step Four: Personalizing Treatment for Patients 

Equipped with this knowledge, Dr. Ingham used CDA funding to partner with researchers from Dana-Farber Cancer Institute to apply the RAD51 assay, a new test that can help doctors identify patients whose tumors have HR defects, even when a detectable genetic alteration is not present. The test might help to personalize sarcoma care by predicting which patients may benefit from pairing olaparib with temozolomide. 
“The RAD51 assay can increase the chances this combination treatment will work and reduce the chance that a patient receives an ineffective therapy that only causes side effects,” said Dr. Ingham. “We found the test was useful in distinguishing patients who had significant benefit from olaparib and temozolomide from those who did not. While more research is needed to further evaluate the utility of this test, the initial results are promising.” 
“Conquer Cancer’s support,” he continued, “motivated me to push forward with this important research despite obstacles, provided me with valuable skills in clinical trial design and conduct, and enabled key correlative work that contributed to the project’s success and spurred interest in the program from collaborators at other institutions and the NCI.” 

Next Steps: A New Clinical Trial 

Dr. Ingham’s donor-funded project has resulted in heightened investment in this niche area of rare cancer research. Based on results from the single-arm phase II study, the NCI approved a randomized phase II/III clinical trial for patients who have uterine leiomyosarcoma and whose disease progressed despite standard care. The study, which recently opened and is enrolling patients, will further assess the effectiveness of olaparib paired with temozolomide versus conventional chemotherapy. 
“It is exciting to see that Conquer Cancer-funded research has led to the development of a new targeted treatment approach that has the potential to change the way we treat a disease currently treated with traditional chemotherapy with limited benefit,” said Dr. Ingham. “If favorable activity is shown in the randomized clinical trial, olaparib and temozolomide could become a new targeted treatment option for patients with this rare and aggressive disease.” 
Bringing new treatments and more hope to patients with rare diseases is at the heart of all Dr. Ingham does to conquer cancer. 
“Donor-funded research is especially important for research in rare cancers,” said Dr. Ingham. “The CDA directly contributed to the success of this research program, and without Conquer Cancer support, the research would not have progressed rapidly to its current stage of development.”

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