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Saturday, March 05, 2011
New Targets and Mechanisms of Resistance

Some weeks the journals seem to be replete with exciting, unexpected, or at least intriguing papers. This has been one of them. Here are a few highlights in translational research published this week.

 

HER2-Like Target for Aggressive Prostate Cancer?

Researchers at the University of Michigan think they've identified a HER2-like therapeutic target in prostate cancer called SPINK1.

 

They already knew that SPINK is overexpressed in approximately 10% of prostate cancer patients and that its expression correlates with shorter biochemical recurrence-free or progression-free survival. Now, in this week’s issue of Science Translational Medicine, the Michigan researchers, led by Arul Chinnaiyan, MD, PhD, Director of the Michigan Center for Translational Pathology and a Howard Hughes Medical Institute Investigator, show that anti-SPINK1 antibodies slowed tumor growth in a xenograft mouse model of prostate cancer.

 

Remarkably, antibodies against the the epidermal growth factor receptor (EGFR), which SPINK1 uses to propogate its oncogenic signal, also slowed growth of the SPINK1-overexpressing tumors.

 

Although neither antibody – or even a combination of the two – completely eradicated the prostate tumors in the mice, the researchers think targeting SPINK1 or EGFR may be valuable in humans.

 

The key, they emphasize, is that such therapies will work only in those patients whose tumors overexpress SPINK1, just like trastuzumab only works in patients whose tumors overexpress HER2.

 

Therefore, future trials designed to test anti-SPINK1 or anti-EGFR therapies must be biomarker driven and restricted to the right group of patients.

 

In fact, the researchers speculate that the reason previous trials with small molecules and antibody inhibitors of EGFR failed in prostate cancer was because they were tested unselected patients. And, they think, the results of a trial with cetuximab support that interpretation: Three (8%) of the 36 patients treated with the cetuximab had partial responses, which is approximately the percentage of prostate cancer patients whose tumors overexpress SPINK1.

 

There are two big caveats  to the current study however. First, the anti-SPINK1 antibody used in the xenograft experiments doesn’t recognize the homologous mouse protein. Therefore, toxicities that might arise with SPINK1 blockade remain completely unknown.

 

Second, the fact that xenograft tumors, which are notoriously easy to cure, shrank but did not disappear after combination treatment with anti-SPINK1 and anti-EGFR antibodies suggests that additional drugs will be needed, even if the group’s overall hypothesis is correct.

 

Nonetheless, the overall message from the paper is that there may be a new therapeutic strategy in the works for a subset of prostate cancer patients.

 

Drs. Tomlins and Chinnaiyan, and co-first author Bushra Ateeq, PhD, are named as inventors on a patent application for SPINK1, and its use in the diagnostic field has been licensed to Gen-Probe Inc. Dr. Chinnaiyan is a consultant for Gen-Probe Inc.

 

Understanding the FBW7 Tumor Suppressor May Guide Therapy in the Clinic Today

Two groups reported in Nature that the FWB7 tumor suppressor protein works through the MCL1 prosurvival protein. Although the groups started with different goals, they converged on the same conclusion. And their conclusions have implications for current therapy

 

In one paper, Ingrid Wertz, MD, PhD, a researcher at Genentech, and colleagues set out to find mechanisms of resistance to anti-tubulin agents. (Several mechanisms of resistance are known, including tubulin mutations and expression of cellular drug pumps, but they aren’t common enough to account for the frequency of resistance in patients.)

 

In normal cells, Wertz and colleagues found that anti-tubulin agents trigger degradation of the MCL1 prosurvival protein, which allows the cells to undergo apoptosis or programmed cell death.

 

That degradation, however, depends on the tumor suppressor protein FBW7. Therefore, tumor cells that lack FBW7 fail to degrade MCL1 protein and survive treatment with anti-tubulin drugs.

 

Based on these data, the authors suggest that profiling patient tumors for FBW7 mutations and MCL1 expression could predict response to anti-tubulin agents. Wertz declined to say, in an interview, if Genentech is developing a commercial assay for FBW7 or MCL1.

 

Meanwhile, researchers in Boston, led by Wenyi Wei, PhD, Assistant Professor of Pathology at Beth Israel Deaconess Medical Center and Harvard Medical School, set out to learn how loss of FBW7 (also called SCFFBW7) contributes to tumor formation.

 

Loss of FBW7 is common in a variety of human cancers including breast and colon cancer  and T-cell acute lymphoblastic leukemia (T-ALL), and deletion of the gene in mice leads to T-ALL.

 

And like, Wertz et al, the Boston group reported that loss of FBW7 increased expression of MCL1. Additionally, depletion of MCL1 with RNA interference slowed progression of T-ALL in FBW7-mutant mice, indicating that MCL1 is critical for FBW7’s tumor suppressive activity.

 

The good news is that the FBW7 mutant T-ALL cells were very sensitive to sorafenib, which has been shown previously to reduce the amount of MCL1 protein. And sorafenib restores sensitivity to ABT-737, a drug designed to trigger apoptosis.

 

The authors of both papers declare they have no competing financial interests. (Dr. Wertz and several other authors are employees of Genentech, and another author on the Wertz paper is an employee at Abbott Laboratories.)

 

Revisiting the “Hallmarks of Cancer”

In 2000, Douglas Hanahan, PhD, and Robert A Weinberg, MD, proposed six hallmarks of cancers that could form a framework for the cancer research. They included sustained proliferation signals, evasion of growth suppressors, resistance to cell death, replicative immortality, ability to induce angiogenesis, and ability to invade tissue and metastasize.

 

They update that framework in the March 4 issue of Cell. (Free full PDF here.)

 

In addition to the six original hallmarks, Drs. Hanahan and Weinberg now add two characteristics that enable the others to occur. These new enabling characteristics are genomic instability and inflammation.

 

Additionally, they recognize that there may be more hallmarks of cancer, which were not apparent at the time of their original paper and are still not set in stone. They include metabolic reprogramming and evasion of immune surveillance.

 

Unlike the original paper, which focused just on the six characteristics of tumor cells, the authors now also discuss the role of the tumor microenvironment and its role in disease.

 

In their concluding remarks 11 years ago, the authors wrote, “One day, we imagine that cancer biology and treatment -- at present, a patchwork quilt of cell biology, genetics, histopathology, biochemistry, immunology, and pharmacology -- will become a science with a conceptual structure and logical coherence that rivals that of chemistry or physics.”

 

As their new review demonstrates, we’ve made progress. But I’m not sure we’ve quite achieved logical coherence. Maybe that’s the next 10 years.

About the Author

Rabiya S. Tuma, PhD
RABIYA S. TUMA, PHD, a Contributing Writer for Oncology Times, is an award winning journalist and a regular contributor to The Economist, and the Journal of the National Cancer Institute. Her work has appeared in a variety of publications including CR Magazine, Yoga + Joyful Living, O The Oprah Magazine, HHMI Bulletin, and the New York Times. Prior to launching her writing career, Rabiya earned her doctorate at the University of Washington and Fred Hutchinson Cancer Research Center and worked at a biotechnology firm in Eugene, Oregon. And though she traded a lab bench for a computer, she remains fascinated with the work that takes basic science into the clinic.

Her OT blog was recognized this year by the American Society of Healthcare Publication Editors (ASHPE) with a bronze award in the category of Best Blog.

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