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From OncoLog, September 2013, Vol. 58, No. 9

Graphic: In Brief

Researchers Identify Inhibitor of Cancer-Promoting Protein Skp2

Researchers have identified a new compound that inhibits the cancer-promoting enzyme Skp2 (or S-phase kinase–associated protein 2).

A team led by Hui-Kuan Lin, Ph.D., an associate professor in the Department of Molecular and Cellular Oncology at The University of Texas MD Anderson Cancer Center, had previously found that Skp2 promotes cancer by marking the cancer-inhibiting protein p27 for destruction and activating a signaling pathway that initiates glycolysis, a primary driver of cancer cell growth and survival.

In research based on these findings, Dr. Lin and Shuxing Zhang, Ph.D., an assistant professor in the Department of Experimental Therapeutics, and their colleagues discovered a compound (SLZ-P1-41) that suppresses the Skp2-related tagging and destruction of p27 and stifles the Skp2 signaling that activates the cancer-feeding glycolysis pathway. The inhibitor works by blocking critical protein binding sites to prevent Skp2 from forming a complex with Skp1; this binding is the initial step in both of Skp2’s cancer-promoting functions.

“Inhibitors often are discovered without an initial understanding of how they work,” Dr. Lin said. “The beauty of this study is that we identified an inhibitor and showed how it functions to block Skp2.”

“This compound [SLZ-P1-41] has a high degree of specificity. Our tests in prostate and lung cancer show it preferentially targets the cancer cells but not the normal cells.”

– Dr. Hui-Kuan Lin

Skp2 has a large area where it interfaces with other proteins, and finding one small molecule that completely blocks a surface of that size is difficult. To identify a compound capable of inhibiting the protein, the researchers used computer models and a database of 10 million compounds.

“To rationally design a drug, you must first understand the target’s biology and then look at its structure and fully comprehend its complex interactions and how disrupting those will help treat the disease,” Dr. Zhang said.

SLZ-P1-41 was first tested against prostate cancer cell lines and normal prostate epithelial cells. The compound selectively killed the cancer cells with minimal effects on the normal tissue. The drug’s effects were confirmed in lung cancer, hepatocellular carcinoma, and osteosarcoma cell lines and in mice bearing human tumor xenografts.

“This compound has a high degree of specificity,” Dr. Lin said. “Our tests in prostate and lung cancer show it preferentially targets the cancer cells but not the normal cells.”

The researchers also found that the inhibitor suppressed the self-renewal of cancer stem cells—which play a role in cancer initiation, progression, and resistance to chemotherapy—in a dose-dependent manner. The study was reported in the journal Cell in August.

Change in CA-125 Level Over Time Shows Promise for Ovarian Cancer Screening

Repeated measurements over time of a woman’s levels of cancer antigen (CA)-125, the protein long recognized for predicting ovarian cancer recurrence, show promise as a screening tool for early-stage ovarian cancer, suggests an ongoing study led by researchers at The University of Texas MD Anderson Cancer Center.

The prospective, single-arm study enrolled more than 4,000 healthy, postmenopausal women with no strong family history of breast or ovarian cancer. The women received a baseline CA-125 blood test and annual tests thereafter. Women whose CA-125 levels demonstrated a sharp elevation at any time underwent transvaginal ultrasonography and were referred to a gynecologic oncologist. Women whose CA-125 levels demonstrated a slight elevation returned for a repeat test in 3 months.

The study’s primary endpoint was the specificity of an increase in CA-125 over time in revealing the presence of ovarian cancer; the researchers found that this specificity was 99.9%.

Only two patients had tumors that were not revealed by increases in CA-125 levels; both had borderline ovarian tumors (tumors of borderline malignancy). One hundred seventeen women were determined to be at high risk by sharp elevations in their CA-125 levels. Of those women, 10 underwent surgery: 4 had invasive ovarian cancer, 2 had borderline ovarian tumors, 1 had endometrial cancer, and 3 had benign ovarian tumors.

Principal investigator Karen Lu, M.D., a professor in and chair of the Department of Gynecologic Oncology and Reproductive Medicine, said that the four invasive ovarian cancers detected by changes in CA-125 were high-grade epithelial tumors, the most aggressive form of the disease. These were caught at early stages, when the disease is treatable and often curable. Dr. Lu also noted that all four women who were found to have invasive disease had been monitored for at least 3 years before a rise in CA-125 level was seen.

These interim results were published online ahead of print in Cancer in August. Dr. Lu said that while encouraging, these findings were neither definitive nor immediately practice-changing. However, Dr. Lu said, “I’m cautiously optimistic that in the not-too-distant future, we may be able to offer a screening method that can detect ovarian cancer in its earliest, curable stages.”

Preclinical Study Finds Origins of Kidney Fibrosis–Causing Cells

Four cell development pathways that lead to kidney fibrosis—uncontrolled, destructive scarring through collagen overproduction—have been pinpointed in mice, according to a study conducted in part at The University of Texas MD Anderson Cancer Center.

Because fibrosis can develop into cancer and enable cancer progression and resistance, preventing or treating fibrosis may be crucial to overcoming certain cancers.

In mouse models of kidney fibrosis, researchers used fate mapping to track which mesenchymal cells would become myofibroblasts, the dominant producers of collagen. In fate mapping, the promoter of a protein expresses a color inside a cell that remains with the cell until it dies, allowing researchers to determine the cell’s origin.

These experiments showed that half of the myofibroblasts came from preexisting resting fibroblasts, 35% came from mesenchymal stem cells originating in the bone marrow, 10% came from blood vessel cells that underwent endothelial-to-mesenchymal transition, and 5% came from kidney cells that underwent epithelial-to-mesenchymal transition.

Contrary to previous studies that implicated pericytes—connective, contractile cells surrounding blood vessels—in myofibroblast generation, this study found that pericytes did not transform into myofibroblasts and that destroying pericytes did not improve kidney fibrosis or alter the production of myofibroblasts. Instead, the differentiation of cells other than fibroblasts into myofibroblasts appeared to rely on transforming growth factor β1.

“Answering a fundamental question about the origin of myofibroblasts by identifying four separate pathways involved in their formation allows us to look at ways to block those pathways to treat fibrosis and potentially prevent future emergence of cancer in some organs,” said Raghu Kalluri, M.D., Ph.D., a professor in and chair of the Department of Cancer Biology and the senior author of the study’s report.

Although the study focused on kidney fibrosis, the researchers believe that their findings will apply to all types of fibrosis. “The sources are likely to be the same for lung or liver fibrosis, but the ratios may be different,” Dr. Kalluri said.

The study’s report was published in the August issue of Nature Medicine.

For more information, talk to your physician, visit, or call askMDAnderson at 877-632-6789.

Other articles in OncoLog, September 2013 issue:


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