Advances in Personalized Medicine: Focus on Prostate and Brain Cancers

May 2012, Vol 3, No 3

Chicago, IL—Targeting prostate cancer with extreme accuracy, using tissue oxygen content to predict its recurrence, and using breast cancer drugs on brain tumors were a few highlights of a news conference on advances in personalized medicine at the 2012 American Association for Cancer Research meeting.

Prostate Cancer

Prostate cancer is the most common cancer in men in the United States. It can be treated equally effectively with surgery or radiotherapy, but approximately 25% of men will develop a recurrence after treatment. “How can we do better? How can we actually tailor treatment more specifically to the needs of these men?” asked Michael Milosevic, MD, FRCPC, Professor of Radiation Oncology and a radiation oncologist in the Princess Margaret Hospital Cancer Program, University Health Network, University of Toronto, Canada.

One answer, he said, is high-precision radiotherapy with intensity-modulated radiation, but it needs to go hand in hand with a better understanding of the biology of prostate cancer. This is where hypoxia comes in. Many tumors contain hypoxic regions that cause the cancer to behave aggressively. Hypoxia drives the spread of cancer and also reduces the effectiveness of therapy.

In a trial of 247 men with prostate cancer, tumor oxygen levels were measured before treatment with high-precision radiotherapy. A follow-up 6.6 years after treatment found that patients with hypoxic tumors did worse than those with well-oxygenated tumors. Hypoxic tumors recurred earlier—usually within 3 to 4 years of completion of treatment.

“Probably the most exciting thing in the context of personalized cancer medicine is the concept that…if we can identify hypoxic tumors, the next step is, can we do something about it? And there are new treatment strategies coming along all the time that specifically target aspects of hypoxia in cancer,” Dr Milosevic said.

Hypoxia can predict prostate cancer recurrence after radiotherapy, and measuring it could help identify the best treatment course. New personalized treatments could then target hypoxia to improve outcomes.

Michael J. Evans, PhD, Research Fellow in the Human Oncology and Pathogenesis Program at Memorial Sloan-Kettering Cancer Center in New York, NY, described his study of noninvasive imaging, which allows clinicians to visualize metastasized prostate cancer and monitor it quantitatively as potential markers, thus advancing the prospect of personalized therapy.

“One of the major unmet clinical needs for the prostate cancer community, as well as for other cancers, is the development of noninvasive imaging markers that can give us some sense of the pathological activation, or the inhibition, of key biologic pathways for the respective cancer,” Dr Evans pointed out.

A radiotracer engineered to locate free prostate-specific antigen (PSA) allows the clinician to assess risk with more accuracy than is available with serum PSA. This tracer, 89Zr-5A10, also allows the study of metastatic bone lesions, which are not yet clearly visible in bone scans. At present, bone scans cannot discriminate between malignant and nonmalignant lesions.

The radiotracer is used in conjunction with positron-emission tomography scans. To date, it has only been tested in mice; investigators hope to stage a human trial by 2013.

Glioblastoma

Ingo K. Mellinghoff, MD, Oncologist, Human Oncology and Pathogenesis Program, Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY, presented his finding that lapatinib (Tykerb), which is approved by the US Food and Drug Administration for use in HER2-positive breast cancer, can potently inhibit epidermal growth factor receptors (EGFR) in glioblastoma. The problem is getting enough drug to the tumor.

As many as 40% of patients with glioblastoma have EGFR mutations. “So the question we are trying to answer in this particular project is, do glioblastoma cells that harbor an extracellular domain mutation require EGFR for survival? Are they addicted to EGFR as are lung cancer and tyrosine kinase mutations? And if so, do they respond to the same type of EGFR inhibitor?” Dr Mellinghoff asked.

Lapatinib and erlotinib (Tarceva; indicated for lung cancer) are both EGFR inhibitors, but only the former inhibits phosphorylation of glioblastoma multiforme cells.

In a large clinical trial, patients with brain tumors received lapatinib before surgery, and tumor specimens were examined after surgery. The specimens showed lapatinib to be a potent inhibitor of EGFRs, but it was not completely effective; some phosphorylation continued. “So it’s good, but it’s not good enough,” said Dr Mellinghoff. What remains to be seen, he said, is how much drug is needed to induce complete cell death. Another trial is being planned, this one using pulsatile lapatinib at intermittent high doses.

“Glioblastoma cells that harbor the extracellular domain are indeed addicted to the EGFR, so there is an opportunity to target this,” Dr Mellinghoff noted.

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