Researchers repurpose existing lung cancer drug to fight ovarian tumors

As is often the case with cancer treatments, many patients are able to benefit from therapy for a time. Tumor activity decreases, scans show improvement, and patient lifespans are prolonged for some period. Following this initial benefit, however, patients frequently develop resistance to treatment sooner than their physician anticipates.

Researchers from Mayo Clinic are now of the opinion that this treatment failure phenomenon may result from the development of drug resistance that occurs quite quickly after the onset of therapy.

Based on newly published findings, ovarian cancer cells activate a protective mechanism immediately after exposure to PARP inhibitors, a type of drug commonly used to treat ovarian cancer. By blocking the early activation of this protective mechanism, scientists demonstrated that the efficacy and duration of PARP inhibitor therapy could be improved.

PARP inhibitors are currently a standard of care for high-grade serous ovarian cancer, which is the most frequent and deadliest subtype of ovarian cancer. More than half of these tumors have a defect in the DNA damage response pathway, typically involving BRCA1 or BRCA2, and are particularly sensitive to the effects of PARP inhibitor therapy.

It is not uncommon, however, for many patients to experience a return of the cancer after an initial response. Prolonged remission occurs in approximately one-third of cases, while most patients experience recurrence within four to sixteen months.

The research by the Mayo Clinic team focused on the earliest phase of treatment, prior to the cellular development of genetic resistance.

"This study provides evidence that the activation of a survival program in cancer cells is not always a gradual development that occurs over time; rather, cancer cells are capable of activating these programs in response to the initial treatment," said Arun Kanakkanthara, Ph.D., an oncology researcher at Mayo Clinic and senior author of the study.

The researchers were interested in this initial response because targeting it could greatly improve the efficacy of existing treatments and potentially mitigate the likelihood of developing resistance. PARP inhibitors were shown to increase the level of the transcription factor FRA1 within treated ovarian cancer cells. FRA1 is responsible for upregulating genes that provide ovarian cancer cells with mechanisms to survive under stress conditions and prevent apoptosis, or cell death.

This increase in FRA1 levels happens very quickly after treatment and remains elevated for three days post-treatment, based on laboratory studies. The researchers found that if FRA1 levels were decreased using gene-editing approaches, the treated cancer cells exhibited increased sensitivity to PARP inhibitors and underwent increased apoptosis. Thus, FRA1 was concluded to be an important component of an adaptive survival response initiated by therapeutic intervention.

The next question that arose was whether an existing medication could disrupt this adaptive survival mechanism. The researchers tested brigatinib, an approved treatment for lung cancer and an ALK inhibitor. They expected that this drug would affect several cellular signaling pathways involved in cancer cell survival. They also expected it would be a successful combination with PARP inhibitors such as olaparib, rucaparib, and niraparib, producing a more substantial impact compared to either medication alone in multiple ovarian cancer cell lines.

When brigatinib was administered in conjunction with one of the PARP inhibitors, the combination had a stronger effect than either drug alone across multiple ovarian cancer cell lines. Additionally, this synergistic effect occurred in ovarian tumors that had or had not been determined to have homologous recombination repair defects, as well as tumors that had developed resistance to PARP inhibitor or platinum chemotherapy.

Notably, when testing the dual therapy on noncancerous human fallopian tube cells in the laboratory, the combination had no adverse effects on healthy human cells. This finding indicates that cancer cells are uniquely susceptible to the treatment due to their specific biological characteristics.

There was a rationale for why brigatinib was effective in this situation. Instead of being active through the traditional DNA damage repair pathway, brigatinib inhibited both focal adhesion kinase (FAK) and EPHA2 signaling molecules at the same time. The findings demonstrated that both pathways work together.

Both signaling molecules are often overexpressed in ovarian cancer and are associated with a poor survival prognosis. Brigatinib rapidly decreased activated levels of FAK and EPHA2, in some cases within an hour of treatment. Thus, inhibiting both pathways at once is essential.

Situations in which both pathways are not blocked do not yield desirable results. However, when both pathways are inhibited simultaneously, tumor cells are less able to defend themselves from damage and become more sensitive to PARP inhibitors.

These data suggest that the two pathways are interconnected and lead to additional downstream effects. Blocking both pathways halts Akt and ERK signaling, resulting in lower levels of FRA1. This impairment reduces the ability of cancer cells to adapt during therapy and results in increased tumor cell death.

Laboratory data may not always translate to animal model systems that mimic patients with ovarian cancer. Therefore, the research group evaluated whether dual treatment was beneficial using patient-derived xenograft mouse models of ovarian cancer. Seven different ovarian cancer xenograft models representing many genetic backgrounds were examined, including those containing BRCA mutations or other DNA repair defects, as well as those that had developed resistance to PARP inhibitors.

Combination treatment with brigatinib and a PARP inhibitor produced a larger decrease in tumor size relative to each individual drug. Combination-treated mice survived longer than single-drug-treated mice. Combination treatment did not appear to be associated with significant toxicity in most mice across studies, except for rare episodes of excessive weight loss.

The findings also demonstrated that not all models exhibited identical therapeutic responses. Animals with tumors lacking homologous recombination defects showed no significant benefit from the combination treatment. This result suggests that ovarian cancer presents a wide degree of biological variability regarding therapeutic indications. However, in some instances, a pattern was noted in the data showing that targeting the early survival response produced an improved therapeutic effect for certain cases.

The authors sought to identify patients who may have a greater therapeutic response. They discovered that tumor models exhibiting high relative levels of both FAK and EPHA2 tended to show strong responses to the combination. A search of The Cancer Genome Atlas database supported this observation.

Patients displaying co-overexpression of both FAK and EPHA2 appear to have a negative prognostic factor for survival in high-grade serous ovarian cancer. Thus, FAK and EPHA2 protein expression could provide a means of identifying patients for inclusion in trial designs testing the combination treatment.

Dr. Weroha concluded: "An ever-present challenge of ovarian cancer research and treatment is resistance. The combination of the insights and knowledge of Dr. Kanakkanthara's group and my clinical experience thus support the preclinical work attempting to target resistance as it develops, as opposed to waiting to treat it after it has developed."

"This will hopefully allow for improved patient outcomes."

The findings of the present article are based on preclinical studies utilizing in vitro and in vivo models of ovarian cancer. They cannot entirely represent the complexities of human tumors. Therefore, the authors indicate that future clinical studies will be necessary to verify that high levels of FAK and EPHA2 expression indicate an enhanced likelihood of response to the combination therapy for women with high-grade serous ovarian cancer.

The authors also plan to conduct a first-in-human trial to assess the safety and efficacy of combining brigatinib with a PARP inhibitor in women with high-grade serous ovarian cancer. If the trial is successful, the combination approach offers an additional potential advantage.

Brigatinib has already received approval from the U.S. Food and Drug Administration for treatment of patients with refractory non-small cell lung cancer, which could reduce the time required for clinical development compared with entirely new chemical entities.

Research findings are available online in the journal Science Translational Medicine.

The original story "Researchers repurpose existing lung cancer drug to fight ovarian tumors" is published in The Brighter Side of News.

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