From Satellite to Street View

Progress in cancer research has delivered a molecular view of malignancy that reveals cancer to be many diseases requiring personalized care.

BY BOB HECKER

When President Nixon signed the National Cancer Act in 1971, he made the conquest of cancer a national crusade. It soon came to be called the “War on Cancer,” a name that promotes cancer as a single disease that affects many parts of the body.

That idea was supported by the relatively limited technology then available, which gave more of a satellite view of cancer. Just as one city looks similar to another from an orbiting satellite, breast cancer cells in one woman looked similar to those in another under the microscope. Yet, while breast cancer was considered one disease, patients often responded differently when given the same treatment, and no one knew why.

Today, new tools and technologies, together with an explosion in computing power, have given science a street-level, molecular view of cancer. Breast cancer, it turns out, is at least five distinct diseases, each marked by a distinct genetic profile. That knowledge helps identify optimal treatments and pinpoint new drug targets.

“Doctors can better predict how a particular breast cancer will respond to different treatment based on molecular subtypes,” says Charles Shapiro, MD, director of breast medical oncology at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

“In the past, chemotherapy was a ‘one size fits all’ treatment for breast cancer. And while chemotherapy is useful against this disease, it often is not selective enough,” Shapiro says. “Research tells us that certain breast cancers, based on their level of gene expression, are more or less responsive to chemotherapy. The more we can target therapies to cancer-cell characteristics, the more effective the therapies will be.”

To the National Cancer Institute (NCI), a greater biological understanding of cancer is a measure of progress, the soil from which new and more effective therapies emerge.

In a report to the president and Congress on The Nation’s Investment in Cancer Research: 2012, NCI Director Harold Varmus, MD, says the document “reflects on a 40-year history of investigation that has brought about profound change … in our understanding of cancer as a complex set of diseases that will require many different lines of investigation about prevention, diagnosis and treatment.”

“When I began to study animal models of cancer in the early 1970s, the collective understanding of (its) origins and progression was negligible; now, we can describe such events in minute detail at the molecular level,” he writes in the Afterword, adding that this knowledge has led to improvements in controlling an increasing number of cancers.

Varmus contends in the NCI’s Cancer Trends Progress Report – 2009-2010 Update that the continued decline in the incidence and mortality rates of lung, prostate, breast and colorectal cancers – the four most common types – is evidence of the nation’s gains against malignancy. The report includes a graph that tracks the incidence of these cancers from 1975-2007.

Yet, nearly 1.53 million Americans were expected to develop some form of cancer in 2010, and 569,000 of them were expected to die from it. Progress in cancer diagnosis, treatment and prevention is hard-won and ongoing. Here are examples of progress in cancer research by OSUCCC – James investigators.

Acute Leukemia

Research led by Clara D. Bloomfield, MD, over her 40-year research career has greatly improved the treatment of patients with acute myeloid leukemia (AML).

“In the 1960s, we didn’t cure anyone with AML. There wasn’t even an intent to treat patients for a cure; AML wasn’t considered a curable disease,” says Bloomfield, a Distinguished University Professor at Ohio State who also serves as cancer scholar and senior adviser to the OSUCCC – James. “Today, we cure about a third of these patients overall, and in some patient groups we cure 70 to 90 percent.”

Early work by Bloomfield showed that the chromosomal abnormalities often seen in AML cells could distinguish patients likely to be cured by standard therapy from those likely to relapse. Since arriving at Ohio State in 1997, one of the many things Bloomfield has worked on is the identification of molecular markers in patients with cytogenetically normal AML (CN-AML), which occurs in 40-45 percent of AML patients and lacks the chromosomal abnormalities that guide therapy in other AML patients.

• Molecular markers identified by Bloomfield and her collaborators now help determine prognosis and guide therapy in patients, as well as define CN-AML subgroups and subtypes. Examples of that work include:


• Discovering the first genetic abnormality in CN-AML, the MLL PTD mutation, in 1994, and that the mutation predicts a poor prognosis; then in 2007, showing that autologous stem cell transplant greatly improves the chance for a cure.


• Discovering that high ERG expression signals poorer survival, even when accompanied by favorable gene markers such as normal FLT3 and mutated NPM1. In 2011, she and her colleagues showed that CNAML patients with TET2 mutations may need aggressive therapy.


• Helping to revise the World Health Organization (WHO) classification of AML in 2001 and again in 2008. Formerly considered one disease, AML now has six subgroups, the largest of which has seven subtypes plus two provisional subtypes, according to the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.


• Serving as senior author on the new internationally accepted European LeukemiaNet Guidelines published in the journal Blood in 2010. This report recommends using cytogenetic and molecular markers from the WHO 2008 reclassification.


• More examples of OSUCCC – James AML research are available here.

Chronic Leukemia

The drugs used to treat chronic lymphocytic leukemia (CLL) over the past 40 years have shown degrees of benefit in patients, but the disease remains incurable despite the number of drugs used to treat it. To help relieve the problem, scientists at the OSUCCC – James are studying novel agents that target specific genetic abnormalities.

“If we can find several agents that strike different targets in CLL cells, they might in combination increase the number of patients who have durable remissions,” says John C. Byrd, MD, director of the Division of Hematology and of the Hematologic Malignancies Program.

Fludarabine is the standard chemotherapy for CLL, but drug resistance often occurs and patients relapse. The only FDA-approved therapy for fludarabine-resistant CLL is alemtuzumab, which can cause a serious drop in white blood cell counts and an increased risk of infections. Byrd, with collaborator Michael Grever, MD, who co-leads the Experimental Therapeutics Program at the OSUCCC – James, is studying several promising possibilities:

• Interim analysis of a 2011 phase II clinical trial led by Byrd indicated that the experimental agent PCI-32765 is highly active and well tolerated in both newly diagnosed and relapsed, drug-resistant CLL patients. The agent is the first to target Bruton’s tyrosine kinase, a protein essential for CLL-cell survival.


• A 2011 multi-institutional study led by Byrd of 104 CLL patients showed that treating CLL patients with the targeted agents rituximab and fludarabine produces remissions lasting 10 years or more in some patients without risk of secondary leukemia.


• A 2009 study showed that a gene called FOX3 is silenced by epigenetic changes early in CLL development, and that therapy to reverse this silencing might delay or prevent CLL progression.


• More examples of OSUCCC – James research in chronic leukemia are available here.

Head and Neck Cancer

In 2000, Maura Gillison, MD, PhD, was first author on a seminal study that strongly linked oral human papillomavirus (HPV) infection and oropharyngeal cancer. A quarter of the tumors analyzed were HPV-positive, and 90 percent of those were positive for HPV16, the cause of cervical cancer. Investigators also found that the HPV-positive patients had about half the risk of death from cancer compared with their HPV-negativecounterparts.

“Our findings strongly suggested this was a distinct type of head and neck cancer that affected people who did not necessarily smoke and drink, whose tumors were largely poorly differentiated and located mainly in the oropharynx, and who had a better prognosis,” says Gillison, a researcher with the OSUCCC – James.

Gillison says those findings revealed a newly recognized oral cancer caused by a major new risk factor: sexually transmitted HPV. Previously, head and neck cancer was thought to be caused largely by tobacco and alcohol.

In a 2010 study published in the New England Journal of Medicine, Gillison and her collaborators determined that the presence of HPV in oropharyngeal tumors is the most important predictor of patient survival. The study showed that HPV in tumors accounts for a better response to therapy, rather than other favorable factors such as young age and small tumors. It suggested that HPV status, along with smoking history and cancer stage, could be used to determine aggressiveness of therapy.

“Previous studies indicated a relationship between HPV in oropharyngeal cancers and patient survival, but they couldn’t determine if other favorable factors were responsible for better outcomes,” Gillison says. “Our findings closed the door on these questions and are allowing the field to move forward with clinical trials to determine how we should use molecular and behavioral factors to personalize therapy.” More examples of OSUCCC – James research in head and neck cancer are available here.

Translational Research

Carlo Croce, MD, director of Ohio State’s Human Cancer Genetics Program, was the first, in 2002, to link microRNA (miRNA) to human cancer. As well as identifying the role of miRNA in cancer, he and his colleagues explore how these small regulatory RNA molecules might be used prognostically, diagnostically and therapeutically. His work ranges over chronic and acute leukemia, multiple myeloma, and thyroid, breast, lung and other human cancers.

• Croce co-led a study that identified patterns of abnormal miRNAs in the plasma of lung cancer patients. The findings could lead to a blood test for lung cancer.


• Croce’s lab has linked three miRNAs – miR-192, miR-194 and miR-215 – to reactivation of the P53 tumor-suppressor gene and to slowing the growth of multiple myeloma cells. The findings provide a rationale for further study of these microRNAs as a treatment for the disease, which has few therapeutic options.


• In a 2005 New England Journal of Medicine paper, Croce and his colleagues showed that they could distinguish between the indolent and aggressive forms of CLL by evaluating the expression pattern of 13 miRNA genes. “It’s vital for oncologists to know which kind patients have so they can properly treat the disease,” Croce says.


• Visit here for more examples of OSUCCC – James microRNA research.

Glioblastoma

Glioblastoma multiforme is the most common and deadly form of brain cancer, with a median survival of 11 months after diagnosis. Arnab Chakravarti, MD, chair of Radiation Oncology and co-director of the OSUCCC – James Brain Tumor Program, is one of several Ohio State cancer investigators working to improve glioblastoma treatment.

• A prospective study of 833 glioblastoma patients reported at the 2011 American Society for Clinical Oncology meeting proves that when a gene called MGMT in tumors is methylated, patients respond better to treatment, says Chakravarti, a coauthor of the study. Overall survival for patients with the methylated gene was 21 months versus 14 months for those with the unmethylated gene. “Testing for MGMT methylation can predict clinical outcomes in glioblastoma patients treated with radiation plus temozolomide,” says Chakravarti, who was the project’s translational-research study chair.


• Glioblastoma is often driven by overexpression of EGFR, but research led by Chakravarti and Markus Bredel, MD, PhD, at the University of Freiburg in Germany, shows that loss of the NFKBIA gene is another important promoter of glioblastoma development. Published in the New England Journal of Medicine, the study found that glioblastomas generally show either abnormally high levels of EGFR or loss of NFKBIA, but not both. “NFKBIA status may be an important predictor of survival and perhaps of treatment outcomes in some glioblastoma patients,” Chakravarti says.


• More examples of OSUCCC – James research in glioblastoma are available here.

Chakravarti notes that gliomas are among the most treatment-resistant of all human tumors. He is working to understand the molecular mechanisms of radiation resistance and to use this knowledge to develop novel therapies.

“Glioblastomas vary in their molecular and genetic makeup and as a result behave differently and require personalized treatment,” Chakravarti says. Pursuing new treatments based on tumor biology will lead to further progress against cancer, he adds.

“As science continues to reveal the true nature of cancer as not one but many diseases that affect individuals differently,” Chakravarti says, “we steadily increase our chances of controlling these maladies and improving the lives of patients.”