Putting the BITE on Melanoma

Highly efficient elimination of melanoma cells expressing melanoma-associated chondroitin sulfate proteoglycan (MCSP) by MCSP/CD3-bispecific chain antibody constructs: A 61.


An engineered antibody-like molecule that binds skin cancer cells to killer T cells, literally tying melanomas to the immune system, could provide a novel therapy for the disease, according to researchers at Micromet, a biotechnology company based in Bethesda, Md., and Munich, Germany. Melanomas are particularly sensitive to T-cell therapies, the researchers say, and their novel antibody construct could be a means of engaging some of the most effective cancer-killing cells in the immune system's arsenal.
These agents are new class of artificial antibodies - what Micromet researchers term a BiTE class (for bispecific T-cell engager) - that are T cell-recruiting antibodies. Essentially, the researchers have linked the binding regions of two specific antibodies together with a short peptide chain.
In this case, one antibody binds to an activating receptor on the surface of killer T cells, called CD3, and the other binds to a protein generally found on the surfaces of skin cancers, called melanoma-associated chondroitin sulfate proteoglycan (MCSP).
"Unlike regular monoclonal antibodies used in cancer therapies, BiTE antibodies can recruit killer T cells for redirected lysis of tumor cells," said Roman Kischel, M.D., director of immunotherapy at Micromet. "By this approach only cells expressing the antigen are attacked by T cells, and we can see target cell lysis at very low picomolar concentrations of BiTE antibodies."
When MCSP-BiTE binds to cancer cells, the cells become visible for any killer T cell passing by. "The T cell will briefly attach to the BiTE-decorated cancer cell and inject its deadly cocktail of killer proteins into the tumor cell," Dr. Kischel said. "This event gears up the T cell to produce more killer proteins and to go into melanoma serial killing mode."
According to Dr. Kischel, the BiTE antibodies do not require specific killer T cells, which may circumvent many limitations of T-cell therapies, such as the mechanisms that some tumors use to escape the immune system and defects in the ability of immune cells to recognize antigen, a frequent problem among cancer patients. Even on the cellular scale, BiTE antibodies are tiny, about a third of the size of conventional antibodies, which Micromet researchers believe may aid by improved tumor penetration in the effectiveness of the therapeutic.
Currently, Micromet researchers are studying similar antibodies specific for B-cell lymphomas in a Phase I trial. The MCSP-BiTE antibodies are now undergoing preclinical studies in cell cultures and animal models.

Daylight PDT for actinic keratoses

Continuous activation of PpIX by daylight is as effective as and less painful than conventional photodynamic therapy for actinic keratoses; a randomized, controlled, single-blinded study
Authors: Wiegell, S.R.; Hædersdal, M.; Philipsen, P.A.; Eriksen, P.1; Enk, C.D.2; Wulf, H.C.
Source: British Journal of Dermatology, Volume 158, Number 4, April 2008 , pp. 740-746(7)
Publisher: Blackwell Publishing
Abstract:
Summary Background
Photodynamic therapy (PDT) is a highly effective treatment for actinic keratoses (AK); however, it is time consuming and often painful for the patient. Daylight-PDT would make the treatment independent of the clinic and less painful due to the continuous activation of small amounts of porphyrins during its formation. Objectives
The objective of this randomized controlled study was to compare response rates and adverse effects after methyl aminolevulinate (MAL)-PDT using conventional red light-emitting diode (LED) light vs. daylight. Patients/methods
Twenty-nine patients with AK of the face and scalp were treated with MAL-PDT in two symmetrical areas. One area was illuminated by red LED light (37 J cm−2) after 3-h incubation with MAL under occlusive dressing. The other area was treated with daylight for 2·5 h after the MAL cream had been under occlusion for half an hour. Results
We found no significant difference in the treatment effect between the two treatments (P = 0·13), with a reduction of AK lesions of 79% in the daylight area compared with 71% in the LED area. Treatment response in the daylight area did not depend on the intensity of the daylight. Illumination with LED was more painful than daylight (P < 0·0001). Erythema and crusting occurred after both treatments and were similar in the two areas. Conclusions
PDT of AK by continuous activation of porphyrins by daylight proved to be as effective as conventional PDT. PDT using daylight activation will make the treatment of these extremely common premalignant tumours more time and cost effective, and more convenient for the patient.

Why dont all moles progress to melanoma

Why dont all moles progress to melanoma

University of Michigan Health System.
Oct 28, 2006 - 12:58:00 PM

ANN ARBOR, Mich. -- Everyone has moles. Most of the time, they are nothing but a cosmetic nuisance. But sometimes pigment-producing cells in moles called melanocytes start dividing abnormally to form a deadly form of skin cancer called melanoma. About one in 65 Americans born this year will be diagnosed with melanoma at some point during their lifetime.

Scientists know that 30 percent of all melanomas begin in a mole. They know that 90 percent of moles contain cancer-causing mutations. What scientists didn't know is how melanocytes stop these mutations from triggering the development of cancer.

Maria S. Soengas, Ph.D., and other scientists in the Multidisciplinary Melanoma Clinic at the University of Michigan Comprehensive Cancer Center, have found the answer to this important question in an unexpected place – a structure inside cells called the endoplasmic reticulum, or ER.

"Our results support the direct role of the endoplasmic reticulum as an important gatekeeper of tumor control," says Soengas, who is an assistant professor of dermatology in the U-M Medical School. "Until now, no one knew there was a connection between ER stress and the very early stages of tumor initiation."

Results of the U-M study – involving melanocytes from normal human skin and biopsies of non-malignant human moles – are being published in the October issue of Nature Cell Biology.

The endoplasmic reticulum is the cell's protein production factory. The process begins when chains of amino acids are deposited in the ER membrane in response to coded instructions from genes. Chaperone proteins fold these amino acids into specific shapes. When too many of them build up in the membrane, or when something goes wrong with the folding process, the system gets bogged down. This can stress or even kill the cell.

To prevent this, the ER sends out distress signals to activate what scientists call the unfolded protein response (UPR). This slows the protein production process and gets rid of excess incoming amino acids, giving the ER a chance to catch up. If that doesn't work, the UPR causes the cell to destroy itself in a process called apoptosis.

"Traditionally, the ER's role was considered to be limited to protein folding or protein modification," Soengas says. "But scientists like Randal Kaufman, a U-M professor of biological chemistry and co-author on our paper, have found that the ER can sense changes in glucose, nutrients, oxygen levels and other aspects of cellular physiology associated with diseases like diabetes and Alzheimer's disease."

"In our study, we found that the ER senses the activity of certain oncogenes in the melanocyte and triggers a response that prevents the malignant transformation of these cells," Soengas adds.

According to Soengas, the tumor suppressive mechanism induced by the ER in melanocytes with these cancer-causing mutations is premature senescence – a form of "suspended animation" that stops the cell cycle and keeps cells from dividing, but doesn't kill them.

"The cells are held in check – they don't die, but they don't proliferate either," Soengas explains. "In the case of moles, melanocytes can stay this way for 20 to 40 years or even your whole life. For most of us, just holding cells in an arrested state is sufficient to prevent the development of cancer. That's why so many people have moles, but few have melanoma."

In the study, U-M scientists found that the tumor suppressive response in melanocytes varied depending on the type of oncogene being expressed in the cell.

"We found that some oncogenes activated the endoplasmic reticulum, while other oncogenes didn't," Soengas says.

In a previous study, Soengas and colleagues found that certain oncogenes use a different senescence mechanism, which doesn't activate the ER, to block the transformation of melanocytes. Both these mechanisms work in addition to or independent from other well-known tumor suppressor mechanisms involving apoptosis.

Soengas says the results of the study will be important in helping scientists understand all the different mechanisms melanocytes use to protect themselves against oncogenes. But she cautions that there are no immediate clinical applications for the study and additional research will be required.

In future research, Soengas will attempt to determine exactly how oncogenes trigger the unfolded protein response in malignant and non-malignant skin cells. "By comparing what happens in normal melanoctyes with what happens in melanoma, we may be able to come up with events that are specific for tumor cells, which could be used for future drug development," she says.

Source:

University of Michigan Health System.

Overcalling of Genital Nevi as Melanomas.

Atypical Genital Nevi
Awareness of a unique subtype of pigmented vulvar lesion will prevent misdiagnosis of melanoma.
Gleason BC et al. Atypical genital nevi. A clinicopathologic analysis of 56 cases. Am J Surg Pathol 2008 Jan; 32:51.

The incidence of pigmented lesions and diffuse hyperpigmentation involving the genitalia is difficult to ascertain, but such lesions can be found in about 10% of white women. Approximately 2% of these are nevocellular nevi (other benign pigmented lesions found here include seborrheic keratoses, melanoses, lentigines, warts, and postinflammatory hyperpigmentation). In general, nevi on the vulva are identical in morphology and histopathology to nevi elsewhere on the body, except for a small subset of nevi in younger women that have the unusual feature of enlarged junctional nests varying in size, shape, and position. Their long-term biologic behavior has not been determined. The histologic and clinical features of these "atypical melanocytic nevi of the genital type" or "atypical genital nevi" (AGN) are the subject of this study.
The authors reviewed hematoxylin- and eosin-stained sections and medical records from 56 cases of AGN. Mean patient age was 26, but four patients were younger than 10 years. Nearly half the lesions were atypical on clinical exam (mean diameter, 6 mm). More than half arose in hair-bearing skin, the rest in glabrous skin or mucosa. In the pediatric group, juxtamucosal or glabrous surfaces (clitoris and labium minus) were the most frequently affected.

The mean follow-up period was 3.5 years. Ten of 17 cases with positive margins had follow-up data available; only 1 of these persisted or recurred, with no further recurrence after complete excision. About 80% of lesions were compound; more than two thirds showed moderate-to-severe cytologic atypia. Ten cases were focal but had pagetoid spread. Adnexal spread and nuclear atypia of the melanocytes situated in the superficial dermis were relatively common. Rare mitoses were identified (maximum, 2 per section). Dermal fibrosis was seen in 45%.

Comment: Melanocytic lesions in the genitalia and along the milk line (axillae, breasts, periumbilical region, and groin) have a tendency to be overdiagnosed as malignant melanomas, a pitfall ascribable to the presence of histologic features usually associated with aggressive biologic behavior. Awareness of this distinct subgroup of pigmented lesions affecting women of reproductive age is essential to avoid unnecessary surgery and patient distress. Although follow-up data on these lesions are limited, among 63 cases in the literature, no metastases have been reported to date.