Novel research makes inroads in cell death pathways

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DENVER—Designer T cells that attack tumors with a vengeance could be the future of prostate cancer treatment. Although the results are very preliminary, the incorporation of designer T cells into prostate cancer treatment led to a significant reduction in PSA levels, according to researchers from Boston University School of Medicine in Providence, R.I.

DENVER-Designer T cells that attack tumors with a vengeance could be the future of prostate cancer treatment. Although the results are very preliminary, the incorporation of designer T cells into prostate cancer treatment led to a significant reduction in PSA levels, according to researchers from Boston University School of Medicine in Providence, R.I.

The study is one of several presented at the AACR meeting that harnessed the power of apoptosis, according to guest editor Owen O'Connor, MD, PhD.

"The area of apoptosis is getting incredibly sophisticated in terms of the kind of biology that people are thinking about: targeting the molecules, trying to sensitize the tumor cells' pro-apoptotic influences by lowering the threshold required to do that," he said.
 

Prostate carcinogenesis

Richard Junghans, MD, PhD, and colleagues created the designer cells by modifying T cells through retroviral gene therapy. The designer T cells express chimeric immune receptors comprising an antibody-based recognition domain combined with T-cell signaling domains to redirect T cells to attached tumor cells based on antibody specificity (abstract 5662).

"Metastatic prostate cancer is incurable. In order to cure this disease, we are going to have to go beyond the current ways of treatment used in the clinic," Dr. Junghans said. "Why T cells? T cells are the perfect killing machine. One T cell, in the space of a day, can kill hundreds of target cells. T cells evolve not to kill cancer cells, but to kill virus-infected cells. What we have to do is fool those T cells into thinking that the cancer cells have a virus."

The phase I trial applied autologous T cells, gene-modified and expanded ex vivo into designer cells that expressed prostate-specific membrane antigen (PSMA).

"We are able to redirect these designer T cells to attack the cancer based on the expression of the PSMA antigen," explained Dr. Junghans, who is the director of the Biotherapeutics Development Lab at the university and chief of the division of surgical research at Roger Williams Medical Center, also in Providence.

Once the T cells were harvested, patients were treated with low-dose interleukin-2, in order to "make room" for the designer T-cells, from day zero to day 28. Two patients were treated at 10Λ9 designer T cell dose. According to the results in the two patients who completed therapy, there was a 50% to 75% reduction in PSA.

Dr. Junghans pointed out several benefits of designer T-cell therapy: the cells are not inert chemicals or molecules but living cells from the patient. Also, while this is an example of personalized medicine, the process itself should have general applicability.

In the next phase of research, Dr. Junghans said that his group will try higher doses of the designer T cells (10Λ10 and 10Λ11) in the hopes of achieving 100% PSA reduction. He also told Oncology News International that he is looking for patient referrals for the next stage of the phase I trial. Ultimately, he said he'd like to have six patients per dose level.

"I'd like to see these T cells considered as drugs," he said. "We can program these T cells to maintain or expand in the presence of tumor and disappear when the tumor is eliminated."
 

Pin1 and pathogenesis

The overexpression of Pin1, a novel regulator of TRF1, may contribute to the downregulation of TRF1 in tumors and play an essential role in regulating telomere maintenance and aging, according to a group from Boston's Beth Israel Deaconess Medical Center.

Pin1 is a peptidyl-prolyl cis-trans isomerase (PPIase) that isomerizes only phosphorylated Ser/Thr-Pro peptide bonds. These Pin1-catalyzed conformational changes after phosphorylation can have profound effects on many key proteins in diverse cellular processes, according to Tae Ho Lee, PhD, and colleagues (abstract 1959).

Pin1 is highly overexpressed in many human cancers and is important for the activation of multiple oncogenic pathways, indicating that Pin1 plays a key role in the pathogenesis of cancer, they stated.

Based on their research, the investigators reported that TRF1 function was regulated by Pin1-mediated prolyl isomerization. Also, Pin1 interacted with the conserved Thr149-Pro motif in TRF1 in a phosphorylation-dependent manner. Moreover, TRF1 expression was decreased and correlated with Pin1 overexpression in human breast cancer tissues, suggesting a close relationship between Pin1 and TRF1 levels under both physiological and pathological conditions.

They said they believe that Pin1 is a novel regulator of TRF1 and its overexpression might contribute to the downregulation of TRF1 in tumors such as breast cancer as well as play an essential role in regulating telomere maintenance and aging.
 

Targeting XIAP

A hallmark of pancreatic cancer is the ability to evade apoptosis. This may be caused by the overexpression of anti-apoptotic proteins such as XIAP. Investigators from the University Children's Hospital Ulm in Heidelberg, Germany, reported that targeting XIAP was an effective approach to breaking Bcl-2-imposed resistance of pancreatic carcinoma towards TRAIL-induced apoptosis, both in vitro and in vivo, without detectable toxicities on normal cells or tissues (abstract 2039).

They noted that XIAP inhibition significantly enhanced TRAIL-induced apoptosis even in Bcl-2 overexpressing pancreatic carcinoma cells, whereas Bcl-2 overexpression protected against TRAIL-induced apoptosis in cells with intact XIAP. In a tumor establishment model in xenograft-bearing mice, XIAP inhibition synergized with TRAIL to suppress pancreatic tumor growth. In a tumor regression mouse model, XIAP inhibition cooperated with TRAIL to trigger caspase-3 activation and apoptosis, causing regression of established pancreatic carcinoma.

Other advances in cell death pathways:

  • A group from the National Jewish Health in Denver and Pharmacyclics in Sunnyvale, Calif., identified two distinct signals originating from the B-cell antigen receptor (BCR) in B-cell lymphomas. In mouse models of non-Hodgkin's lymphoma, they focused on BCR-derived signal effectors that are important for the maintenance of NHL tumors, especially Bruton's tyrosine kinase (Btk), a non-receptor tyrosine kinase required for antigen-triggered, BCR-dependent signaling. They showed that Btk expression was required for the survival of murine NHL-like tumors in vitro and that tumor cells deficient in Btk fail to expand in vivo and that targeting Btk may be a viable therapeutic strategy (abstract 1984).
  • Researchers from the University of Texas Health Science Center in Tyler identified novel death receptor agonists, which inhibited cell viability and colony formation, and which induced apoptosis in androgen-dependent (LNCaP) and independent (PC-3) human prostate cancer cell lines, but had no effect on human normal prostate epithelial cells and hepatocytes. The combinations of DRAs with TRAIL had additive effects on apoptosis in prostate cancer cells. Commonly used anticancer drugs further enhanced the apoptosis-inducing potential of death receptor agonists, they stated (abstract 2035).
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