Re-examining Cancer

UC San Diego Moores Cancer Center researchers push the envelope

For more than 40 years, medical science has waged a steady, expensive war against cancer, with mixed results. The overall death rate from cancer is down — dropping approximately 1 percent a year since 1990. Still, almost 575,000 Americans die from the disease annually.

Cancer is, in fact, many diseases. It’s different in every patient. It defies easy explanation. To find answers, researchers must sometimes re-examine their data and assumptions, promote provocative positions or simply demand things be done differently.

Meet Three such scientists:
Michael Karin, Thomas Kipps and Razelle Kurzrock

Michael Karin

Michael Karin, PhD

"Researchers need to work on developing non-invasive methods to monitor the presence and development of prostate cancer."
- Michael Karin, PhD

For men of a certain age, prostatespecific antigen (PSA) screening is almost a rite of passage. It’s a simple blood test, easily done, but if PSA levels are deemed too high, the next step is frequently a biopsy — the actual plucking of tissue from the prostate, a walnut-sized gland located just below the bladder.

Prostate biopsies are not casually conducted. They can be painful and involve complications, but health experts have long argued that their potential benefit — an accurate assessment of the presence and scope of any cancer in the prostate — outweighs their risks and potential problems.

But what if the biopsy actually makes the cancer worse?

Michael Karin, PhD, Distinguished Professor of Pharmacology at UC San Diego School of Medicine, is one of biomedical science’s most-cited authors, notably for his pioneering research elucidating how inflammation can fuel the development and growth of tumors.

Much of this work has involved explaining how chronic conditions like obesity generate immune responses that aid and abet cancer cell survival and growth. But Karin and colleagues have also gathered evidence indicating that inflammation also promotes the progression of prostate cancer to a more aggressive and incurable disease. Such inflammation could be initiated by a prostate biopsy.

“Our findings suggest that promoting inflammation of the cancerous tissue can hasten progression to metastatic disease, in which the cancer is spread to other parts of the body,” Karin said. “We have shown that the proteins produced by inflammatory cells are the ‘smoking gun’ behind prostate cancer metastasis.”

Karin and colleagues hope to soon launch clinical trials of a drug that ablates inflammatory B cells, improving prostate cancer therapy.

“I think the biochemical research community needs to work on developing non-invasive methods to monitor the presence and development of prostate cancer,” Karin said. “Until such methods are available, we have to count on biopsies. But, we need to minimize the risk of infection and inflammation caused by the biopsy procedure.”

Thomas Kipps, MD, PhD

"CLL is a complex and confounding disease. If we untangle its secrets, we have clues to the secrets of other cancers."
- Thomas Kipps, MD, PhD

Thomas Kipps

Chronic lymphocytic leukemia (CLL ) is a cancer of the blood and bone marrow, characterized by the growth of abnormal white blood cells that ultimately crowd out healthy cells, wreaking havoc on the immune system. Patients weaken, increasing the chance they will develop severe or life-threatening complications.

Like all cancers, CLL is distinct. Nonetheless, says Thomas Kipps, MD, PhD, professor of medicine and deputy director of research at UC San Diego Moores Cancer Center, CLL might hold the key to understanding and treating many kinds of cancer, including solid tumors.

Kipps has spent almost three decades investigating and treating CLL. He is among the nation’s leading experts in the disease and serves as director of the multi-institutional CLL Research Consortium, based at UC San Diego.

“CLL is a complex and confounding disease,” said Kipps, “but its basic biology and nature make it the low-hanging fruit on the tree of cancer discovery. If we untangle its secrets, we have clues to the secrets of many other cancers.”

An Important Cancer Model

Several factors make CLL a pre-eminent cancer model.

First, it can be diagnosed easily and early, based on simple blood tests. That makes studying it comparatively uncomplicated. “Unlike solid tumor research, in which there’s often no easy access to the primary tumor except through surgery, we can focus direct, repeated and regular attention on CLL cells by just taking a blood sample,” Kipps said.

Second, CLL tends to grow slowly. Some patients lack symptoms for years, even decades. Initial treatment is often to simply watch and wait, which means researchers and doctors can focus on investigating fundamental, still unresolved questions: What caused the cancer? How does it progress? What changes, when and where? Why does the same cancer behave differently in different patients?

“The opportunity to do research is important,” said Kipps. “In acute leukemias and other cancers that typically act and kill quickly, there is little time to reflect upon the nature of the disease or study it. Your most pressing goal is to save the patient.”

Last, CLL appears to share many qualities with solid tumor cancers, such as sarcomas, carcinomas and lymphomas. “In fact, much of what we’ve learned about solid tumors in recent years derives from leukemia research.”

For example, Kipps and colleagues discovered in 2004 that microRNAs — short sequences of ribonucleic acid that turn on and off hundreds of different genes — play a major role in causing CLL. “No one had previously suspected microRNAs,” he said.

In 2010, Kipps followed up with colleagues David Cheresh, PhD, Sudarshan Anand, PhD, and others at UC San Diego Moores Cancer Center, identifying a microRNA that regulated blood vessel growth, which is essential to the development and spread of tumors.

Of course, a better understanding of CLL doesn’t eliminate the need for continued research into solid tumors and other cancers. “The war on cancer has many fronts,” Kipps said. But CLL presents an unrivaled path for progress — and perhaps an eventual victory.

Razelle Kurzrock, MD

Razelle Kurzrock, MD

Razelle Kurzrock

Imagine that you tried treating pneumonia with insulin, says Razelle Kurzrock, MD, the senior deputy director for clinical science at UC San Diego Moores Cancer Center.

“It wouldn’t work, and you might soon come to the conclusion that insulin was a bad drug, which it obviously isn’t. It’s a very effective treatment for diabetes. It’s just wrong for pneumonia.”

Something similar happens daily with the search for new cancer treatments. Every year, scores of compounds and molecules with suspected anti-cancer properties are tested in long, complex clinical trials — looking to narrow down candidates to the very few with the broadest therapeutic effect. It often doesn’t matter if benefits are marginal, at best.

In the process, Kurzrock said countless drug candidates that might significantly benefit a small subset of patients are ignored or discarded, perhaps lost forever. Nowhere is that reality more obvious and painful than in the long fight against cancer.

As scientists have painstakingly parsed its secrets, they have learned one lesson over and over: It’s never the same enemy. Mutations and causative factors vary by cancer type and patient, and a therapy that works wonders in one person may be ineffective or worse in another.

With the rise of translational medicine, advances in diagnostic technologies and the imminent prospect that patients may soon have their genomes sequenced quickly and cheaply, the need to account for individual variation is becoming paramount. It requires a revolution in thinking, and Kurzrock is one of the thought leaders.

Targeted, Personalized, Medicine

Before coming to Moores Cancer Center last year, Kurzrock developed a hugely successful Phase 1 clinical trials program at the University of Texas MD Anderson Cancer Center that emphasized targeted, personalized medicine.

Called PREDICT (Profile-Related Evidence Determining Individualized Cancer Therapy), the approach employs leading-edge molecular technologies to identify specific mutations in patients — Kurzrock calls them “actionable abnormalities” — and uses that information to match patients to the drugs and treatments most likely to work for them.

“The potential for greater efficacy is huge,” she said, “because we’ll know what works for different situations. We’ll understand the mechanisms involved, which means fewer adverse side effects.”

This brings us back to the way clinical trials are conducted. Instead of focusing on the drug, she says, trials need to focus on strategy, testing how to best combine diagnoses with drug combinations. “Every person, in effect, becomes his or her own trial.”

Kurzrock wants Moores Cancer Center to be at the forefront of this effort. She concedes there are a lot of hurdles, not least among them how to approve drugs if every patient effectively receives a different treatment. But she believes these challenges can be resolved and that they must be resolved.

“I think we’re almost set for a revolution in cancer care,” she said. “In 10 or 20 years, people will look back and wonder why we thought this was so novel.”