New Targeted Therapy Delivers Chemo Directly to Ovarian Cancer Cells

Using a protein, called EphA2, researchers at the University of Texas M. D. Anderson Cancer Center have successfully delivered chemotherapy in a highly selective manner in preclinical models of ovarian cancer.

EphA2 is attractive for such molecularly targeted therapy because it is over expressed in ovarian and other cancers, including breast, colon, prostate and non-small cell lung cancers and in aggressive melanomas, and its expression has been associated with a poor prognosis.

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Ovarian cancer affects both the ovaries and is referred to as the 'silent killer' as the symptoms go unnoticed until the disease advances.

"One of our goals has been to develop more specific ways to deliver chemotherapeutic drugs. Over the last several years we have shown that EphA2 is a target that is present quite frequently in ovarian and other cancers, but is either present in low levels or is virtually absent from most normal adult tissues.

EphA2's preferential presence on tumour cells makes it an attractive therapeutic target," said senior author Dr. Anil K. Sood, from the Departments of Gynecologic Oncology and Cancer Biology at M. D. Anderson.

For the study, the researchers used a carrier system to deliver chemotherapy directly to ovarian cancer cells.

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The immunoconjugate contains an anti-EphA2 monoclonal antibody linked to the chemotherapy drug monomethyl auristatin phenylalanine (MMAF) through the non-cleavable linker maleimidocaproyl.

It has been shown that auristatins induce cell cycle arrest at the G - M border, disrupt microtubules and induce apoptosis (programmed cell death) in cancer cells.

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The researchers examined the delivery system's specificity in EphA2-positive HeyA8 and EphA2-negative SKMel28 ovarian cancer cells through antibody-binding and internalization assays.

In addition, they assessed viability and apoptosis in ovarian cancer cell lines and tumour models and examined anti-tumour activity in orthotopic mouse models with mice bearing HeyA8-luc and SKOV3ip1 ovarian tumours.

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A monoclonal antibody linked to a chemotherapy drug, showed substantial antitumor activity in ovarian cancer cell lines and in mice.

Sood said that the immunoconjugate was highly specific in delivering MMAF to the tumour cells that expressed EphA2 while showing minimal uptake in cells that did not express the protein.

In the models, the therapy inhibited tumour growth in treated mice by 85 percent - 98 percent compared to control mice.

"Once we optimized the dosing regimen, the drug was highly effective in reducing tumour growth and in prolonging survival in preclinical animal models.

We actually studied bulkier masses because that is what one would see in a clinical setting where there are pre-existent tumours, and even in this setting the drug was able to reduce or shrink the tumours," said Sood.

The findings of the study have been published in the latest issue of the Journal of the National Cancer Institute.

Source-ANI
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