Treating vascular disorders with a cell-based strategy

ScienceDaily (Oct. 18, 2012) — A new approach for generating large numbers of circulatory system cells, known as vascular endothelial cells (VECs), from human amniotic-fluid-derived cells (ACs) is reported in a study published by Cell Press October 18th in the journal Cell. The strategy, which shows promise in mice, opens the door to establishing a vast inventory of VECs for promoting organ regeneration and treating diverse vascular disorders.

"Currently, there is no treatment available for a broad range of patients with vascular diseases, including patients who have suffered heart attack, stroke, lung diseases, trauma, emphysema, or even diabetes and neurological disorders," says senior study author Shahin Rafii of Weill Cornell Medical College. "Replacing injured or dysfunctional endothelial cells with normal cultured endothelial cells could potentially provide for a novel therapy to treat these diseases that afflict millions of patients worldwide."

VECs line the entire circulatory system, including the heart and blood vessels, and they help to control blood pressure, promote the formation of new blood vessels, and support the regeneration and repair of injured organs. A wide range of vascular diseases stem from dysfunctions in VECs, so generating healthy cells for transplantation in patients would represent an attractive treatment strategy. But past stem cell strategies have fallen short: VECs derived from stem cells are unstable and tend to convert to nonvascular cells, and they do not increase rapidly in number, limiting their potential for clinical use.

To overcome these limitations, Rafii and his team developed a safe approach for producing a large number of stable VECs from amniotic cells, which are extracted during routine amniocentesis procedures and thus represent a steady source of cells. To reprogram amniotic cells into mature and functional VECs, called rAC-VECs, the researchers turned specific genes on and off using members of the E-twenty-six family of transcription factors -- proteins that bind DNA and are important for VEC development.

The rAC-VECs resembled human adult VECs in that they expressed the normal set of vascular-specific genes. When rAC-VECs were transplanted into the regenerating livers of mice, they formed stable, normal, and functional blood vessels. "This major breakthrough will allow the use of endothelial cells for the treatment of numerous vascular disorders and may benefit a myriad of patients," Rafii says.

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The above story is reprinted from materials provided by Cell Press, via EurekAlert!, a service of AAAS.

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Journal Reference:

Michael Ginsberg, Daylon James, Bi-Sen Ding, Daniel Nolan, Fuqiang Geng, Jason M. Butler, William Schachterle, Venkat R. Pulijaal, Susan Mathew, Stephen T. Chasen, Jenny Xiang, Zev Rosenwaks, Koji Shido, Olivier Elemento, Sina Y. Rabbany, Shahin Rafii. Efficient Direct Reprogramming of Mature Amniotic Cells into Endothelial Cells by ETS Factors and TGFß Suppression. Cell, 2012; DOI: 10.1016/j.cell.2012.09.032

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Researchers study 'ACT TIL' approach to treating metastatic melanoma

ScienceDaily (Oct. 17, 2012) — Researchers at Moffitt Cancer Center have carried out a clinical trial in which patients with metastatic melanoma were given chemotherapy and an immunotherapy of adoptive cell transfer (ACT) with tumor infiltrating lymphocytes (TIL). Tumor tissues were surgically removed from patients, minced and grown in culture. The treatment combined chemotherapy, then ACT with TIL, followed by interleukin-2 (IL-2). The combination therapy drew a high response rate from some patients.

The study appears in the October issue of the Journal of Immunotherapy.

"Our purpose was to demonstrate the feasibility of performing TIL growth and the efficacy of ACT TIL therapy using techniques developed at the National Cancer Institute," said Amod Sarnaik, M.D., assistant member of the Cutaneous Oncology Department at Moffitt. "Combining chemotherapy with ACT and high dose IL-2 resulted in a 38 percent objective response rate in patients with metastatic melanoma."

"Although our clinical study successfully met its goal of demonstrating that ACT TIL therapy could be offered to advanced melanoma patients, strategies to improve on its feasibility and efficacy are under way," said Shari A. Pilon-Thomas, Ph.D., assistant member of the Immunology Program at Moffitt. "Combination therapies that enhance the proliferation and function of TIL are being explored."

A second-generation ACT TIL trial is enrolling patients at Moffitt.

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Vegetable-derived compound effective in treating triple-negative breast cancer, research suggests

ScienceDaily (Oct. 17, 2012) — A new compound created from a rich source in vegetables including broccoli and brussel sprouts has been developed to combat triple-negative breast cancer (TNBC). This research is being presented at the 2012 American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition, the world's largest pharmaceutical sciences meeting, in Chicago, Ill., on Oct. 14 -- 18, during Breast Cancer Awareness Month.

TNBC accounts for approximately 15-20 percent of all breast cancer cases in the U.S. It is one of the most aggressive forms of breast cancer; it grows faster, spreads to other parts of the body earlier, is harder to detect on a mammogram and recurs more often.

Mandip Sachdeva, Ph.D. and Chandraiah Godugu, P.h.D. from Florida A&M University, in collaboration with Stephen Safe, Ph.D., from Texas A&M University, have evaluated the activity of novel C-substituted diindolylmethane (C-DIM) derivatives and demonstrated that they have superior anticancer activities. Sachdeva's study reveals that these synthetic compounds derived from diindolylmethane (DIM), commonly found in various types of cruciferous vegetables, can be used to treat several types of cancer, including triple-negative breast cancer. C-DIMs are also being investigated for their cancer prevention activity.

"Targeted treatment options for TNBC are limited; current treatments, such as infusions, result in poor patient compliance and increased toxicity," said Sachdeva. "We are confident that the compounds we are currently working with are an effective treatment for triple-negative breast cancer. These compounds are safer for the patient than current treatments available."

In contrast to existing anticancer drugs, the diindolylmethane compounds are orally active, so they could be available to patients in pill form and safe to take daily. When taken in combination with existing anticancer drugs, the diindolylmethane compounds can effectively decrease the number of treatments a patient receives.

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