(BPT) - Connie Bell’s journey with low-grade serous ovarian cancer (LGSOC) began unexpectedly in her 30s. Residing in Madison, Wisconsin, Connie was 36 when she first noticed her unusual symptoms, which she and her gynecologist initially dismissed as being related to existing conditions like interstitial cystitis and irritable bowel syndrome. But her symptoms, which included mild pelvic pain and two unusually heavy, painful periods, persisted. It wasn’t until several months later, after multiple medical visits, tests, and escalating concerns, that she ultimately received a devastating diagnosis of LGSOC, a rare ovarian cancer. This diagnosis, however, was merely the first step in what continues to be an extensive and challenging journey for Connie and many others with LGSOC.

LGSOC, a rare, insidious, and persistent type of ovarian cancer that has an alarming ability to adapt and persist despite current treatments, such as standard chemotherapy, due to its distinct molecular and histopathological profile. Unfortunately, approximately 85% of people with LGSOC will have their cancer recur. Compounding this issue is the absence of FDA-approved therapies tailored specifically for LGSOC, which underscores a tremendous gap in patient care. In response to these challenges, researchers are actively pursuing new therapeutic approaches.

Leading these efforts is Verastem, a biopharmaceutical company dedicated to innovating therapies for difficult-to-treat cancers like LGSOC. Their focus is on RAS/MAPK pathway, a crucial cellular system that fuels the aggressiveness and treatment-resistance of LGSOC, and many other, tumors. Through these innovations, Verastem aims to offer renewed hope to patients like Connie, who urgently need better LGSOC treatments and a greater assurance that their cancer will not return after remission.

People with LGSOC face obstacles in detection and treatment

While current prevalence estimates for low-grade serous carcinoma are not available, it has been estimated that LGSOC represents less than 10% of new epithelial ovarian cancer cases and presents unique complexities that severely hinder diagnosis and treatment. One of the factors that sets LGSOC apart from the more common high-grade serous ovarian cancer (HGSOC) is its impact on younger women. Diagnosed as early as the 20s and 30s, it can often inflict devastating consequences on fertility. But, despite its early presentation, LGSOC typically isn’t diagnosed until its advanced stages when treatment options are limited. This is because, as with Connie Bell, it can begin with easy-to-overlook symptoms like bloating, back pain, and menstrual irregularities, which can delay an accurate diagnosis.

“My original gynecologist was not initially concerned, but thankfully ordered an ultrasound which revealed a suspicious cyst. A follow-up MRI revealed widespread malignancy, at which point she still didn’t think it was cancer but referred me to a cancer center to be sure,” describes Connie. “It was there that a gynecologic oncologist recognized the seriousness and scheduled me for surgery to remove the tumors.”

But Connie still wasn’t clear on her diagnosis. “I entered surgery without knowing whether or not I would wake up with a cancer diagnosis, and I didn't find out that it was the low-grade serous form until two weeks after my surgery,” said Connie.

Even after an accurate diagnosis is made, people with LGSOC face another daunting journey — finding the right treatment. Treatment options for LGSOC are extremely limited because these tumors harbor distinct biological complexities that make them slow yet persistently growing, inherently less responsive to standard chemotherapy, and highly prone to returning even after achieving remission.

Yet, despite these critical distinctions, patients with LGSOC are often treated with the same regimens as other cancers, such as the standard treatments used for HGSOC, leaving many feeling like they’re receiving “treatment leftovers” instead of therapies tailored to their specific needs. This disparity primarily stems from a long-held misunderstanding of LGSOC’s unique requirements, as it was only officially recognized as a distinct form of ovarian cancer in 2014.

Like many others with LGSOC, Connie's condition and its treatment journey have had a tremendous impact on her daily life. "I have three nieces and a nephew I can't keep up with anymore," she said. "It's just so sad to me that I'm missing out on those different experiences and life events, that I feel like my life is forever changed and that I'll have to be on medication for the rest of my life. This is my new normal, and I have to learn to deal with it."

However, new treatment strategies targeting the molecular intricacies of LGSOC aim to bridge long-standing treatment gaps and offer a brighter “new normal.”

The potential of RAS/MAPK targeting therapies

The RAS/MAPK pathway plays a pivotal role in cell growth and development. However, mutations in RAS genes can drive uncontrolled cell growth and tumor formation, which occurs in an astounding ~30% of all human cancers and a whopping ~70% of LGSOC cases.

Unfortunately, while the prominent role of RAS in driving cancer has been widely known for over three decades, many therapeutic approaches have proven unsuccessful. This is because cancer cells can find alternative ways through the RAS/MAPK pathway to bypass their therapeutic effects.

Verastem is pioneering new approaches to address these issues with their lead candidate, avutometinib. This investigational first-of-its-kind RAF/MEK clamp is designed to block multiple parts of the RAS pathway simultaneously in a single molecule. This multi-pronged approach aims to deliver a more effective and durable solution against adaptive drug resistance issues that have hindered RAS-targeted therapies for years.

In addition, Verastem is developing another drug, defactinib, which targets selective FAK signaling — a separate mechanism that cancer cells use to evade RAS/MAPK-targeting therapies.

The investigational combination has already shown potential benefits for patients with LGSOC as part of Verastem’s RAMP (Raf And Mek Program) and is currently being investigated in the confirmatory Phase 3 RAMP 301 study (GOG-3097; ENGOT-ov81/NCRI).

Exploring a novel combination therapy with RAMP 301

The international Phase 3 RAMP 301 study aims to determine if the novel combination of avutometinib and defactinib may provide clinical benefits compared to standard treatments for recurrent LGSOC. The trial is seeking approximately 270 patients with recurrent LGSOC who have undergone prior platinum-based therapy and whose disease has progressed.

The study, conducted by gynecological cancer specialists, will measure the effectiveness, safety, and quality of life measures of the investigational combination.

If you or a loved one are interested in learning more about this study, please visit: LGSOCstudy.com