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Photoacoustic Tomography

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Imaging-based Cancer Patient Management, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Nanotechnology for Drug Delivery, tagged , , , , , , , , , , , , , , , on July 27, 2013| 1 Comment »

Author: Tilda Barliya PhD

Photoacoustic Tomography (PAT), also called the optoacoustic or thermoacoustic (TA), is a materials analysis technique based on the reconstruction of an internal photoacoustic source distribution from measurements acquired by scanning ultrasound detectors over a surface that encloses the source under study. Moreover, it is non-ionizing and non-invasive, and is the fastest growing new biomedical method, with clinical applications on the way.

Dr. Lihong Wang, a Distinguished Professor of Biomedical Engineering in the School of Engineering and Applied Science at Washington University in St. Louis, summarizes the state of the art in photoacoustic imaging (1).

The photoacoustic (PA) effect:

The fundamental principle of the PA effect can be simply described: an object absorbs EM radiation energy, the absorbed energy converts into heat and the temperature of the object increases. As soon as the temperature increases, thermal expansion takes place, generating acoustic pressure in the medium. However, a steady thermal expansion (time invariant heating) does not generate acoustic waves; thus, the heating source is required to be time variant.

Dr. Wang explains that “the trick of photoacoustic tomography is to convert light absorbed at depth to sound waves, which scatter a thousand times less than light, for transmission back to the surface. The tissue to be imaged is irradiated by a nanosecond-pulsed laser at an optical wavelength”.

Absorption by light by molecules beneath the surface creates a thermally induced pressure jump that launches sound waves that are measured by ultrasound receivers at the surface and reassembled to create what is, in effect, a photograph.

When comparing to other modalities, PAT has several great advantages:

Table 1 Comparison of imaging modalities.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Dr. Wang is already working with physicians at the Washington University School of Medicine to move four applications of photoacoustic tomography into clinical trials (2).

  • One is to visualize the sentinel lymph nodes that are important in breast cancer staging;
  • A second to monitor early response to chemotherapy;
  • A third to image melanomas;
  • The fourth to image the gastrointestinal tract.

Sentinel node biopsy provides a good example of the improvement photoacoustic imaging promises over current imaging practice. Sentinel nodes are the nodes nearest a tumor, such as a breast tumor, to which cancerous cells would first migrate.

Currently, sentinel node biopsy, includes injection of  a radioactive substance, a dye or both near a tumor. The body treats both substances as foreign, so they flow to the first draining node to be filtered and flushed from the body. A gamma probe or a Geiger counter is used to locate the radioactive particles and the surgeon must cut open the area and follow the dye visually to the sentinel lymph node.

Dr. Wang however, offers a simpler method: injecting an optical dye that shows up so clearly in photoacoustic images that a hollow needle can be guided directly to the sentinel lymph node and a sample of tissue taken through the needle.

Contrast agents:

Most photoacoustic (PA) contrast agents are designed for absorbing laser, especially in the NIR spectral range. However, RF contrast agents are also desirable due to the superior penetration depth of RF in the body (1).  A typical example is indocyanine green (ICG), a dye approved by FDA. ICG has high absorption in the NIR spectral region, and it has already been proved to increase the PA signal when it is injected in blood vessels. Most recently, methyline blue was used as the contrast agent to detect the sentinel lymph node (SLN) (4).

Compared with dyes, nanoparticles possess a high and tunable absorption spectrum, and longer circulation time (1). The absorption peak is tunable by changing the shape and size of the particle. In addition, nanoparticles can be used to target certain diseases by bio-conjugating them with proteins, such as antibodies.  Among different nanoparticles, gold nanoparticles are favored in optical imaging due to their exceptional optical properties in the visible and NIR spectral ranges, including scattering, absorption and photoluminescence. So far, none of the gold nanoparticles have been approved by FDA (1).

One exciting aspect of photoacoustic tomography is that images contain functional as well as structural information because color reflects the chemical composition and chemistry determines function. Photoacoustic tomography, for example, can detect the oxygen saturation of hemoglobin, which is bright red when it is carrying oxygen and turns darker red when it releases it (3), that is important, since almost all diseases, especially cancer and diabetes, cause abnormal oxygen metabolism.  For example see image 1.

Image courtesy of Junjie Yao/Lihong Wang

Image 1: melanoma tumor (MT) cells were injected into a mouse ear on day 1. By day 7, there were noticeable changes in the blood flow rate (top graph, right) and the metabolic rate of oxygen usage (bottom graph, right). Counterintuitively, the tumor did not increase the oxygen extraction fraction (middle graph). The colors correspond to depth, with blue being superficial and red deep (3).

Wang’s team demonstrated that oxygen metabolism betrayed the presence of a melanoma within few days of injections in animal models, where as Oxygen use doubled in a week.

In this aspect: photoacoustic images,  can offer several parameters such as;

  • Vessel cross-section,
  • Concentration of hemoglobin and blood flow speed,
  • and The gradient of oxygen saturation can be used to calculate the oxygen use by a region of tissue.

Analysis of oxygen use is not necessarily new and is frequently measured by positron emission tomography (PET), which requires the injection or inhalation of a radioactively labeled tracer and undesirable radiation exposure.

Photoacoustic Tomography is currently being investigated for (5):

  1. Breast cancer (microvascular).  Additionally, for further information on photoacoustic tomography please read the article by Dr. Venkat Karra (I).
  2. Skin cancer (melanin)
  3. Brain tumors
  4. Cardiac disease – myocardial infraction (6)
  5. Ophthalmology – retinal disease (7)
  6. Ostheoarthrities (8)

Summary

photoacoustic tomography perfectly complements other biomedical imaging modalities by providing unique optical absorption contrast with highly scalable spatial resolution, penetration depth, and imaging speed. In light of its capabilities and flexibilities, PAT is expected to play a more essential role in biomedical studies and clinical practice.

Reference:

1.  Changhui Li and Lihong V Wang. Photoacoustic tomography and sensing in biomedicine. Phys. Med. Biol. 2009 54 R59 doi:10.1088/0031-9155/54/19/R01  http://iopscience.iop.org/0031-9155/54/19/R01 http://iopscience.iop.org/0031-9155/54/19/R01/pdf/0031-9155_54_19_R01.pdf

2. Jiecheny Yin. Photoacoustic tomography in cancer detection. http://bme240.eng.uci.edu/students/08s/jiecheny/index.htm

3. Jim Goodwin. NEW IMAGING TECHNIQUE COULD SPEED CANCER DETECTION. http://www.siteman.wustl.edu/ContentPage.aspx?id=5788

4.  Song K H, Stein E W, Margenthaler J A and Wang L V. Noninvasive photoacoustic identification of sentinel lymph nodes containing methylene blue in vivo in a rat model J. Biomed. Opt. 2008: 13 054033–6.  http://oilab.seas.wustl.edu/epub/SongK_2008_J_Biomed_Opt_13_054033.pdf

5. Junjie Yao and Lihong V Wang.  Photoacoustic tomography: fundamentals, advances and prospects. Contrast Media Mol Imaging. 2011 September; 6(5): 332–345. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205414/

6. Holotta M, Grossauer H, Kremser C, Torbica P, Völkl J, Degenhart G, Esterhammer R, Nuster R, Paltauf G, Jaschke W. Photoacoustic tomography of ex vivo mouse hearts with myocardial infarction. J. Biomed Opt. 2011 Mar;16(3):036007. doi: 10.1117/1.3556720. http://www.ncbi.nlm.nih.gov/pubmed/21456870

7. Hao F. Zhang, Carmen A. Puliafito, and Shuliang Jiao, Photoacoustic Ophthalmoscopy for In Vivo Retinal Imaging: Current Status and Prospects.  Ophthalmic Surg Lasers Imaging. 2011 July; 42(0): S106–S115.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291958/

8. Yao Sun, Eric S. Sobel, and Huabei Jiang. First assessment of three-dimensional quantitative photoacoustic tomography for in vivo detection of osteoarthritis in the finger joints.  Med. Phys. 38, 4009 (2011); http://dx.doi.org/10.1118/1.3598113 . http://online.medphys.org/resource/1/mphya6/v38/i7/p4009_s1?isAuthorized=no

Other articles from our Open Access Journal:

I. By : Venkat Karra. Visualizing breast cancer without X-rays. http://pharmaceuticalintelligence.com/2012/05/08/visualizing-breast-cancer-without-x-rays/

II. By: Dr. Dror Nir. Ultrasound in Radiology – Results of a European Survey. http://pharmaceuticalintelligence.com/2013/07/21/ultrasound-in-radiology-results-of-a-european-survey/

III.  By: Dr. Dror Nir. Causes and imaging features of false positives and false negatives on 18F-PET/CT in oncologic imaging. http://pharmaceuticalintelligence.com/2013/05/18/causes-and-imaging-features-of-false-positives-and-false-negatives-on-18f-petct-in-oncologic-imaging/

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FDA approved two drugs and a companion diagnostic test for the treatment of advanced or unresectable cutaneous melanoma patients

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, tagged , , , , , , , on June 1, 2013| 4 Comments »

Reporter: Ziv Raviv, PhD

FDA Approves BioMerieux’s BRAF Test as CDx, www.genomeweb.com

The FDA has very recently (May 29, 2013) approved two new drugs to treat unresectable and metastatic melanoma. Both drugs are inhibitors of B-Raf which is frequently mutated in melanoma (1). The new drugs are products of GlaxoSmithKline (GSK): Dabrafenib (marked as Tafinlar), a B-Raf inhibitor aimed to treat melanoma patients harboring V600E mutation (2), and Trametinib (marked as Mekinist), a MEK inhibitor that was shown in phase III clinical trials to be efficient for treating melanoma patients with BRAF V600E or V600K mutations (3). Both drugs are given orally and approved as single agents. About 75,000 new cases of melanoma are being diagnosed in the US and above 9,000 people die from the disease, each year. Until recently metastatic melanoma was considered an incurable disease with very poor prognosis and limited survival rates. These new two drugs are now joining the first two drugs approved in 2011 to treat metastatic melanoma that are already in clinical use – vemurafenib (Zelboraf) which is also a B-Raf inhibitor (4), and ipilimumab (Yervoy). The introduction of the two drugs was co-approved in concert with the THxID BRAF test from BioMérieux. This PCR-based BRAF test is designed to determine whether a melanoma patient harbors the V600E or V600K BRAF gene mutation and will assist directing the correct treatment to be given to patients. This BRAF mutation test is the second companion diagnostic approved for BRAF mutation detection following the approval of Roche’s cobas 4800 BRAF V600 Mutation Test in August 2011. Overall, the association of diagnostics with treatments as approved in this case is another step further in the ongoing efforts invested by pharmaceutical and diagnostic companies toward establishing personalized medicine to treat cancer patients.

Resources:

FDA press release

GenomeWeb report

References

  1. Mutations of the BRAF gene in human cancer. Davies H et al. Nature. 2002 Jun 27;417(6892):949-54.
  2. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomized controlled trial. Hauschild A et al. Lancet. 2012 Jul 28;380(9839):358-65.
  3. Improved survival with MEK inhibition in BRAF-mutated melanoma. Flaherty KT et al. N Engl J Med. 2012 Jul 12;367(2):107-14
  4. Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation. Chapman PB et al. N Engl J Med. 2011 Jun 30;364(26):2507-16

Related articles on this Open Access Online Scientific Journal

  1. Whole exome somatic mutations analysis of malignant melanoma contributes to the development of personalized cancer therapy for this disease. Author: Ziv Raviv PhD
  2. In focus: Melanoma Genetics. Curator: Ritu Saxena, PhD
  3. In focus: Melanoma therapeutics. Author and Curator: Ritu Saxena, PhD

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Association between Non-melanoma Skin Cancer and subsequent Primary Cancers in White Population

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, tagged , , , , , on April 24, 2013| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

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Word Cloud By Danielle Smolyar

Risk of a Second Primary Cancer after Non-melanoma Skin Cancer in White Men and Women: A Prospective Cohort Study

  • Fengju Song,
  • Abrar A. Qureshi,
  • Edward L. Giovannucci,
  • Charlie S. Fuchs,
  • Wendy Y. Chen,
  • Meir J. Stampfer,
  • Jiali Han mail
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Abstract

Background

Previous studies suggest a positive association between history of non-melanoma skin cancer (NMSC) and risk of subsequent cancer at other sites. The purpose of this study is to prospectively examine the risk of primary cancer according to personal history of NMSC.

Methods and Findings

In two large US cohorts, the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS), we prospectively investigated this association in self-identified white men and women. In the HPFS, we followed 46,237 men from June 1986 to June 2008 (833,496 person-years). In the NHS, we followed 107,339 women from June 1984 to June 2008 (2,116,178 person-years). We documented 29,447 incident cancer cases other than NMSC. Cox proportional hazard models were used to calculate relative risks (RRs) and 95% confidence intervals (CIs). A personal history of NMSC was significantly associated with a higher risk of other primary cancers excluding melanoma in men (RR = 1.11; 95% CI 1.05–1.18), and in women (RR = 1.20; 95% CI 1.15–1.25). Age-standardized absolute risk (AR) was 176 in men and 182 in women per 100,000 person-years. For individual cancer sites, after the Bonferroni correction for multiple comparisons (n = 28), in men, a personal history of NMSC was significantly associated with an increased risk of melanoma (RR = 1.99, AR = 116 per 100,000 person-years). In women, a personal history of NMSC was significantly associated with an increased risk of breast (RR = 1.19, AR = 87 per 100,000 person-years), lung (RR = 1.32, AR = 22 per 100,000 person-years), and melanoma (RR = 2.58, AR = 79 per 100,000 person-years).

Conclusion

This prospective study found a modestly increased risk of subsequent malignancies among individuals with a history of NMSC, specifically breast and lung cancer in women and melanoma in both men and women.

Please see later in the article for the Editors’ Summary

Editors’ Summary

Background

In the United Kingdom and the United States, about one in three people develop cancer during their lifetime and, worldwide, cancer is responsible for 13% of all deaths. Primary cancer, which can develop anywhere in the body, occurs when a cell begins to divide uncontrollably because of alterations (mutations) in its genes. Additional mutations allow the malignancy to spread around the body (metastasize) and form secondary cancers. The mutations that initiate cancer can be triggered by exposure to carcinogens such as cigarette smoke (lung cancer) or the ultraviolet (UV) radiation in sunlight (skin cancers). Other risk factors for the development of cancer include an unhealthy diet, physical inactivity, and alcohol use. In the United States, the most common cancer is non-melanoma skin cancer (NMSC). Although more than 2 million new cases of NMSC occur each year, fewer than 1,000 people die annually in the United States from the condition because the two types of NMSC—basal cell carcinoma and squamous cell carcinoma—rarely metastasize and can usually be treated by surgically removing the tumor.

Why Was This Study Done?

Some studies have suggested that people who have had NMSC have a higher risk of developing primary cancer at other sites than people who have not had NMSC. Such a situation could arise if exposure to certain carcinogens initiates both NMSC and other cancers or if NMSC shares a molecular mechanism with other cancers such as a deficiency in the DNA repair mechanisms that normally remove mutations. If people with a history of NMSC are at a greater risk of developing further cancers, a specific surveillance program for such people might help to catch subsequent cancers early when they can be successfully treated. In this prospective cohort study, the researchers examine the risk of primary cancer according to personal history of NMSC in two large US cohorts (groups)—the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS). The HPFS, which enrolled 51,529 male health professionals in 1986, and the NHS, which enrolled 121,700 female nurses in 1976, were both designed to investigate associations between nutritional factors and the incidence of serious illnesses. Study participants completed a baseline questionnaire about their lifestyle, diet and medical history. This information is updated biennially through follow-up questionnaires.

What Did the Researchers Do and Find?

The researchers identified 36,102 new cases of NMSC and 29,447 new cases of other primary cancers from 1984 in white NHS participants and from 1986 in white HPFS participants through 2008. They then used statistical models to investigate whether a personal history of NMSC was associated with a higher risk of subsequent primary cancers after accounting for other factors (confounders) that might affect cancer risk. A history of NMSC was significantly associated with an 11% higher risk of other primary cancers excluding melanoma (another type of skin cancer that, like NMSC, is linked to overexposure to UV light) in men and a 20% higher risk of other primary cancers excluding melanoma in women; a significant association is one that is unlikely to have happened by chance. The absolute risk of a primary cancer among men and women with a history of NMSC was 176 and 182 per 100,000 person-years, respectively. For individual cancer sites, after correction for multiple comparisons (when several conditions are compared in groups of people, statistically significant differences between the groups can occur by chance), a history of NMSC was significantly associated with an increased risk of breast and lung cancer in women and of melanoma in men and women.

What Do These Findings Mean?

These findings suggest that there is a modestly increased risk of subsequent malignancies among white individuals with a history of NMSC. Although the researchers adjusted for many confounding lifestyle factors, the observed association between NMSC and subsequent primary cancers may nevertheless be the result of residual confounding, so it is still difficult to be sure that there is a real biological association (due to, for example, a deficiency in DNA repair) between NMSC and subsequent primary cancers. Because of this and other study limitations, the findings reported here should be interpreted cautiously and do not suggest that individuals who have had NMSC should undergo increased cancer surveillance. These findings do, however, support the need for continued investigation of the apparent relationship between NMSC and subsequent cancers.

Additional Information

Please access these Web sites via the online version of this summary athttp://dx.doi.org/10.1371/journal.pmed.1​001433.

Citation: Song F, Qureshi AA, Giovannucci EL, Fuchs CS, Chen WY, et al. (2013) Risk of a Second Primary Cancer after Non-melanoma Skin Cancer in White Men and Women: A Prospective Cohort Study. PLoS Med 10(4): e1001433. doi:10.1371/journal.pmed.1001433

Academic Editor: Eduardo L. Franco, McGill University, Canada

Received: September 11, 2012; Accepted: March 15, 2013; Published: April 23, 2013

Copyright: © 2013 Song et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by US NIH CA87969 and CA055075. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: AQ declares the following: Pfizer – Questionnaire licensed for clinical trials; research grant. Merck – Questionnaire licensed for clinical trials. Amgen – Research grant. Abbott – Consulting. US Centers for Disease Control – Consulting. Janssen – Consulting. Novartis – Consulting. All other authors have declared that no competing interests exist.

Abbreviations: AR, absolute risk; BCC, basal cell carcinoma; BMI, body mass index; HPFS, Health Professionals Follow-up Study; MV, multivariate; NER, nucleotide excision repair; NHS, Nurses’ Health Study; NMSC, non-melanoma skin cancer; RR, relative risk; SCC, squamous cell carcinoma; UV, ultraviolet

Introduction

Non-melanoma skin cancer (NMSC) is the most common cancer in the United States. It consists mainly of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Its incidence has been rapidly increasing over the past several decades and the incidence rate was about 6,000/100,000 in the year 2006 [1]. NMSC has a low mortality rate of 1/100,000 [2], but its high prevalence and the expense of related treatment make NMSC a major public health problem and place it among the costliest cancers in the United States [3]. Individuals with personal history of NMSC may be at an altered risk for developing other primary cancers[4]–[11]. One view is that sunlight causes NMSC but also produces vitamin D, which in turn may reduce the risk of other cancers [12]. Another view is that NMSC and other cancers may share common carcinogenic exposures or molecular mechanisms in their etiology, such as DNA repair deficiency and immune suppression, and thus the history of NMSC may indicate an increased risk of subsequent cancer development.

Previous studies suggest a positive association between personal history of NMSC and risk of subsequent cancer at other sites [4]–[11]. Most previous reports, however, were based on cancer registry data without adjustment for potential confounding lifestyle factors [4]–[10]. The only cohort study was limited by its sample size and lacked adequate power to assess individual cancer sites [11]. We carried out a cohort analysis to evaluate the association between personal history of NMSC and subsequent malignancy in the Nurses’ Health Study (NHS) and the Health Professionals’ Follow-up Study (HPFS).

Methods

Ethics Statement

Our study was approved by the Human Research Committee at the Brigham and Women’s Hospital with written informed consent from all participants.

Study Population

The NHS was established in 1976, when 121,700 registered nurses aged 30–55 y in 11 US states responded to a baseline questionnaire regarding risk factors for cancer. Participants completed self-administered, mailed follow-up questionnaires biennially with updated information on their lifestyle, diet, and medical history. The HPFS began in 1986 when 51,529 US male health professionals, including dentists, veterinarians, pharmacists, and optometrists aged 40–75 y, completed a baseline questionnaire on lifestyle, diet, and newly diagnosed diseases. The information was updated biennially with follow-up questionnaires. The follow-up rates of the participants in both cohorts exceed 90%. These studies were approved by the Human Research Committee at Brigham and Women’s Hospital. Race was self-identified in this study as White, Asian, African American, and others. Only white participants were included in this study, accounting for 95.6% of the total population in the two cohorts. The rationale for focusing the primary hypothesis on white participants only was that the patterns of incidence (and likely the risk factors) for NMSC differ widely by race.

Identification of NMSC and Other Primary Cancers

We have routinely identified cases of NMSC and other primary cancers in both cohorts (from 1984 in the NHS and from 1986 in the HPFS). Participants reported new diagnoses biennially. With their permission, participants’ medical records were obtained and reviewed by physicians to confirm their self-reported diagnosis. Medical records were not obtained for self-reported cases of BCC, because the validity of BCC self-reports was more than 90% in validation studies in our cohorts in early years [13],[14]. The personal history of pathologically confirmed invasive SCC and self-reported BCC was the exposure in this analysis. The study outcome was the occurrence of the first confirmed primary cancer other than NMSC. All other cancer cases were documented by medical records or death certificates, and only confirmed cases were included in the analysis.

Assessment of Covariates

Covariates in this analysis included age (continuous variable), body mass index (BMI) (<21, 21–23, 23–25, 25–27, 27–29, 29–31, >31), physical activity (quintiles), smoking status (never, past 1–14 cigarettes per day, past 15+ cigarettes per day, current 1–14 cigarettes per day, current 15+ cigarettes per day), multi-vitamin use (yes or no), menopause status and hormone replacement therapy use in women (pre-menopause, post-menopause non-user, post-menopause past user, and post-menopause current user), and physical examination in the last 2 y (yes or no). We asked about the location of residence (US states) at birth and at age of 15 and 30. The 50 states (and the District of Columbia) were divided into three ultraviolet (UV) index groups: 5 or less (low UV index); 6 (medium UV index); and 7 or more (high UV index)[15]. We defined participants in these three groups if they resided in the same UV-index region at birth, age of 15 and 30.

Statistical Analysis

Follow-up began in 1984 for the NHS and 1986 for the HPFS when the diagnosis of NMSC was first routinely collected, and follow-up ended in 2008 for both cohorts. Participants who reported a history of cancer (including NMSC) prior to baseline were excluded. Participants contributed person-time from the date of return of the baseline questionnaire (1984 in NHS and 1986 in HPFS) until date of diagnosis of confirmed primary cancer, date of death, or the end of follow-up (May 31, 2008), whichever came first. For those who were lost to follow-up, we censored them at the return date of the last questionnaire. Cox regression analysis with time-dependent covariates was used to determine the relative risks (RRs) and 95% CIs of second primary malignancies associated with a previous NMSC diagnosis. We calculated age-standardized absolute risks (ARs) of second primary malignancies associated with a previous NMSC diagnosis. NMSC diagnosis could change during the follow-up period. For individuals with no personal history of cancer at baseline who went on to be diagnosed with NMSC as a first cancer diagnosis during follow-up, the follow-up period before the NMSC diagnosis contributed person-time to the non-exposure group, and the follow-up period after the NMSC diagnosis contributed person-time to the exposure group. Age was coded as a continuous variable in all the analyses. We showed overall cancer risk with and without melanoma. We performed several secondary analyses. We excluded those diagnosed with other primary cancers within the first 4 y of NMSC diagnosis to minimize the detection bias. We examined BCC and SCC history separately. We performed stratified analysis according to age (≤60 y, >60 y), UV-index of residence at birth, age 15, and age 30 (≤5, = 6, ≥7), smoking status (never smoker, past smoker, current smoker), and BMI (<25, 25–30, ≥30). We coded these factors as dummy variables and tested their interactions with the history of NMSC individually. We tested multiplicative interaction terms by the likelihood ratio test comparing the model with the cross-product terms with the model containing just the main effects of these factors and the history of NMSC along with the same covariates.

We assessed the association between NMSC diagnosis and risk of developing site-specific cancers that were diagnosed in more than 100 patients in each cohort. For individual cancer sites, the Cox models additionally included risk factors specific for some cancer sites. We included additional covariates in the multivariate models for breast, ovarian, endometrial, prostate cancers, and melanoma. The Bonferroni correction for p-value was applied for multiple comparisons for individual cancer sites among men and women, calculated as 0.05/n (n = 28). Statistical analyses were conducted using SAS software (version 9, SAS Institute). All statistical tests were two-sided.

Results

Characteristics of our study population according to a personal history of NMSC in mid-point of the follow-up (1998) are shown in Table 1. Participants with a history of NMSC were more likely to be older and tended to burn and have more severe sunburns. Participants with history of NMSC diagnosis were more likely to have red or blonde hair and to reside in high UV-index states. Other characteristics were similar between the exposure group and the non-exposure group.

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Table 1. Characteristics according to personal history of non-melanoma skin cancer in 1998.

doi:10.1371/journal.pmed.1001433.t001

We followed the HPFS participants from 1986 to 2008, for a total of 833,496 person-years. During this period, 1,577 cases of SCC, 10,422 cases of BCC, and 10,590 primary cancer cases other than NMSC were recorded. The mean time for the development of a primary cancer after NMSC was 116±47 mo. We followed the NHS from 1984 to 2008 (2,116,178 person-years) during which 2,322 cases of SCC, 21,781 cases of BCC, and 18,857 primary cancer cases other than NMSC were recorded. The mean time for the development of a primary cancer after NMSC was 156±71 mo.

A personal history of NMSC was associated with a higher risk of other primary cancers in men (RR = 1.15; 95% CI 1.09–1.22, p<0.0001) and women (RR = 1.26; 95% CI 1.21–1.31,p<0.0001) (Table 2). The association attenuated slightly when melanoma was excluded from the outcome in the analysis, but remained significant in men (RR = 1.11; 95% CI 1.05–1.18, p= 0.0007) and in women (RR = 1.20; 95% CI 1.15–1.25, p<0.0001). Age-standardized AR was 176 in men and 182 in women per 100,000 person-years. The association remained significant after we excluded those diagnosed with other primary cancers within the first 4 y of NMSC diagnosis in men (RR = 1.15; 95% CI 1.05–1.25) and women (RR = 1.19; 95% CI 1.11–1.28). In men, the association was significant according to BCC diagnosis (RR = 1.17; 95% CI 1.10–1.24) but not SCC diagnosis (RR = 1.01; 95% CI 0.87–1.17). In women, the association was significant for both BCC (RR = 1.25; 95% CI 1.20–1.30) and SCC diagnosis (RR = 1.24; 95% CI 1.10–1.39). We compared people with personal history of SCC with people with personal history of BCC on their risk of developing subsequent cancer, and no significant differences were found (Table S1). In addition, we have compared SCC in situ group with invasive SCC group and the group of SCC or BCC; the results are shown in Table S2. Compared to those with history of invasive SCC or those with history of SCC or BCC, individuals with history of SCC in situ were less likely to develop subsequent cancers. Such risk reduction was significant among women.

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Table 2. Overall and stratified analysis of risks of total subsequent primary cancers according to personal history of non-melanoma skin cancer in men and women.

doi:10.1371/journal.pmed.1001433.t002

No substantial differences were found in the stratified analysis according to age, UV-index, or BMI. When stratified by smoking status, significant associations were found in never-smokers (RR = 1.19; 95% CI 1.08–1.31 in men, and RR = 1.28; 95% CI 1.20–1.38 in women) and past smokers (RR = 1.12; 95% CI 1.03–1.22 in men, and RR = 1.27; 95% CI 1.20–1.35 in women), but not in current smokers (RR = 1.05; 95% CI 0.75–1.46 in men, and RR = 1.10; 95% CI 0.97–1.23 in women). The p-value for interaction was 0.046 for men and women combined.

For individual cancer sites (Table 3), a history of NMSC was associated with an increased risk of prostate cancer in men (RR = 1.11; 95% CI 1.02–1.20, p = 0.01). The age-standardized AR was 137 per 100,000 person-years. The RR was similar for fatal prostate cancer (RR = 1.17; 95% CI 0.89–1.53). A history of NMSC was also associated with an increased risk of melanoma in men (RR = 1.99; 95% CI 1.63–2.43, p<0.0001). The age-standardized AR was 116 per 100,000 person-years. In women, a history of NMSC was associated with an increased risk of breast cancer (RR = 1.19; 95% CI 1.11–1.28, p<0.0001; AR = 87 per 100,000 person-years), lung cancer (RR = 1.32; 95% CI 1.14–1.52, p = 0.0002; AR = 22 per 100,000 person-years), leukemia (RR = 1.30; 95% CI 1.00–1.69, p = 0.05; AR = 7 per 100,000 person-years), kidney cancer (RR = 1.48; 95% CI 1.10–1.99, p = 0.01; AR = 8 per 100,000 person-years), and melanoma (RR = 2.58; 95% CI 2.34 –2.98, p<0.0001; AR = 79 per 100,000 person-years). After taking into account the multiple comparisons for individual cancers (n = 28), the associations with breast cancer, lung cancer in women, and melanoma in both men and women remained significant. We analyzed SCC and BCC history separately for individual cancer sites. We observed different rates for second cancer development according to personal history of SCC and BCC. However, no statistically significant heterogeneity (p for heterogeneity ranged from 0.16 to 0.88) was found for any cancer site between BCC and SCC due to the limited power (Table S3).

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Table 3. Risks of subsequent primary cancers at different sites according to personal history of non-melanoma skin cancer in men and women.

doi:10.1371/journal.pmed.1001433.t003

Discussion

To the best of our knowledge, this is the largest prospective study on this topic. In this study, a total of 36,102 cases of NMSC and 29,447 cases of cancers other than NMSC were documented. Among those with a personal history of NMSC, we found a 15% increased risk in men and a 26% increased risk in women of developing a second primary cancer, compared with those who had no such history. A systematic review summarizing previous studies revealed that NMSC is associated with more than 10% increased risk of subsequent primary cancer in registry-based studies and nearly 50% increased risk in cohort studies [16]. Our study has extended previous findings by adding a prospective analysis in two large US cohorts with more than two decades of follow-up. The unique aspects of our study included stratified analyses by other risk factors, disentanglement of surveillance bias, and comprehensive adjustment for potential confounders.

It was speculated that the association between NMSC and subsequent cancer risk may be different among people living in locations with different UV-indexes. Specifically, southern regions have solar UV-B radiation levels that provide sufficient vitamin D to reduce the risk of cancer incidence, and thus inverse associations were more likely to be found. On the contrary, studies that found positive associations were mostly conducted in northern regions where UV-B radiation levels do not provide sufficient vitamin D [17],[18]. In our analysis stratified by UV-index, no substantial differences were found for the associations between NMSC and cancer risk among locations with different UV-indexes. To the extent that some cancers have been suggested to be reduced with higher vitamin D [19], it might be worth noting the fact that while colorectal cancer was not increased in this study, it was not decreased as would be expected if NMSC were a marker for sunlight and thus vitamin D exposure.

Intensified medical surveillance of persons with a history of NMSC is unlikely to explain the increased cancer incidence observed in our study. In our analysis, we adjusted for physical examination in the last 2 y, and the result changed little. After we excluded those diagnosed with other primary cancers within the first 4 y of NMSC diagnosis, the association remained significant. Compared to those with history of invasive SCC or with history of SCC or BCC, individuals with history of SCC in situ were less likely to develop subsequent cancers. These results suggested that the patients who carried NMSC precursors but did not develop skin cancers might be either less genetically susceptible or have lower exposure. In addition, for prostate cancer, the association remained significant for fatal prostate cancer. Furthermore, several cancers that we observed associations with are not ones that would be detected on routine screening. Moreover, at least one study that assessed deaths rather than cancer incidence also found increased cancer mortality in people with history of NMSC [20].

Several studies have observed an increased risk of NMSC after other cancers. In one study, chronic lymphocytic leukemia patients had an increased risk of death due to NMSC (RR = 17.0, 95% CI 14.4–19.8) [21]. In another study, among 14 different sites for first primary malignancies, 11 of these sites including prostate, breast, and leukemia were followed by an increased risk of skin cancer (for SCC, RR of 14.1 for males and 14.6 for females) [22]. However, while treatment of these primary cancers may predispose to subsequent skin cancers, most of the NMSC cases are cured by surgical excision without any systemic chemotherapy, and radiation, and their concomitant side effects, including possible carcinogenicity. In addition, the similarity between the age-adjusted and multivariate-adjusted RRs demonstrated that the observed association between NMSC and subsequent cancers is unlikely to be explained by confounding from smoking, obesity, vitamin use, exercise, or any of the other measured risk factors that we controlled for.

The link between NMSC and risk of other cancers is likely to represent an etiologic association. For melanoma especially, the link may be due to sun exposure. For other cancers, while there are several explanations [23]–[28] of the association between NMSC and the risk of subsequent cancer, studies have found that certain genetic markers underlying skin cancer are also associated with other cancer types [29]. It is biologically plausible that deficiencies of pathways responsible for protecting against cellular transformation in multiple tissues, such as DNA repair or immune responses, may act systemically and play a role in cutaneous and internal carcinogenesis.

Humans have evolved several DNA repair pathways dealing with damage [30]. The nucleotide excision repair (NER) pathway is responsible for the repair of a wide variety of DNA damage that leads to distortion of the DNA helix. Such bulky DNA adducts include UV-induced photoproducts, smoking-related benzo(a)pyrene diolepoxide (BPDE)-DNA adducts, and other DNA damage induced by chemical carcinogens. Reduced capacity of the NER has been shown to confer susceptibility to certain cancers in the general population, including melanoma, BCC, SCC, SCC of head and neck, lung cancer, breast cancer, and bladder cancer[31]–[34]. Personal history of NMSC may be a marker of susceptibility due to reduced DNA repair capacity and it may predict the risk of subsequent cancer development.

The NER activity has been shown to be tissue-specific. For example, relatively low NER efficiency was observed in oral tissues [35]. Both rapidly proliferating tissues (e.g., kidney) and slowly proliferating tissues (e.g., lung) exhibit higher demand for NER capacity upon stimulation to proliferation [36]. The DNA repair system consists of several distinct pathways with many subcomponents, each interacting and overlapping with one another in order to achieve genomic stability and high fidelity. Some tissues, such as breast, lack redundant systems of DNA repair that are present in other tissues [37],[38]. Defects in DNA repair would be expected to have greater impact in such tissues without extensive DNA repair redundancy. In addition, a number of studies have suggested a role of sex hormone (e.g., estrogen and androgen) in the regulation of DNA repair activity in breast and prostate cancers [39]. After correction for multiple comparisons for individual types of cancers, the significant association remained for breast cancer, lung cancer in women, and melanoma in both men and women. Even though the positive associations are biologically plausible, we cannot rule out the possibility of chance findings for each individual cancer site.

In our analysis stratified by smoking status, significant association was found among never and past smokers. Because the NER enzymes recognize bulky DNA adducts including both UV-induced photoproducts and smoking-related BPDE-DNA adducts, the interaction between smoking status and history of NMSC highlights the potential role of the NER pathway in the development of second cancers. However, the effect of inherited insufficient capacity of the NER indicated by history of NMSC is only apparent among non-current smokers and for lung cancer in women. Further mechanistic investigation is warranted.

Sub-optimal immune surveillance could be another common susceptibility factor for both cutaneous and internal cancers. Malignant progression is accompanied by profound immune suppression that interferes with an effective antitumor response and tumor elimination [40]. Impaired immunity has been implicated as a non-site-specific determinant of cancer risk [41]. In addition, UV radiation can also cause immunosuppression. UV exposure adversely affects the skin immune system by diminishing antigen-presenting cell function, inducing immunosuppressive cytokine production, and modulating contact and delayed-type hypersensitivity reactions [42],[43], all of which can reduce the body’s surveillance for tumor cells [44],[45]. UV suppresses immune reactions locally, but can also affect the immune system in a systemic fashion when higher UV doses are given [46],[47]. UV radiation affects immune surveillance by modulating the balance between an effective immune response and immune tolerance of an emerging cancer [41]. We did not observe an association between UV-index and the risk of cancer except for skin cancer in our study, which makes this explanation less likely for our findings.

The identification of BCC cases in this study was based on self-report without pathological confirmation. However, the participants in the two cohorts were nurses and health professionals. The validity of their reports was expected to be high, and it has been proven in our validation studies [13],[14]. In addition, previous studies of BCC in the NHS using the self-reported cases identified both constitutional and sun exposure risk factors as expected, such as lighter pigmentation, less childhood and adolescent tanning tendency, higher tendency to sunburn, and tanning salon attendance [48],[49]. We recently confirmed the MC1R gene as the top BCC risk locus using the NHS and HPFS samples [50]. These data together suggest that the bias due to self-report of BCC is likely to be minimal in our study. Moreover, the potential under-report of BCC diagnosis would be expected to bias observed associations toward the null, and such bias would not explain the positive associations that we found.

The strengths of our study included the prospective cohort design and updated assessment of cancer diagnosis and other risk factors every 2 y, more than two decades of follow-up, and a large number of incident skin cancer cases. We had detailed data on related covariates for stratified analyses and comprehensive adjustment for potential confounders. All the participants were health professionals, minimizing potential confounding by educational attainment or differential access to health care. Nevertheless, we cannot completely exclude residual confounding, and our findings may not assign causality. Although the observed significant associations in breast cancer, lung cancer in women, and melanoma in both men and women remained significant after correction for multiple comparisons, we cannot absolutely rule out chance findings for individual cancer sites, and the underlying mechanism for the associations found in specific cancer sites is not entirely clear. In addition, the significant associations for some individual cancers did not meet the adjusted p-value threshold because of their limited sample size.

We cannot estimate the recurrence rate of NMSC or subsequent cancer risk among people with multiple NMSC because we only recorded the first report of each type of skin cancer in both cohorts. We do not have data for non-whites in this study, and our results cannot be generalized to non-whites owing to the dramatic difference in skin cancer incidence among different races. In summary, we observed a modestly increased risk of other cancers among individuals with a history of NMSC. Because our study was observational, these results should be interpreted cautiously and are insufficient evidence to alter current clinical recommendations. Nevertheless, these data support a need for continued investigation of the potential mechanisms underlying this relationship.

SOURCE:

http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001433;jsessionid=55BB9D9B87F79FF1CA7594C56F407F14

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Whole exome somatic mutations analysis of malignant melanoma contributes to the development of personalized cancer therapy for this disease

Posted in Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, tagged , , , , , , , , , , on April 23, 2013| 3 Comments »

Whole exome somatic mutations analysis of malignant melanoma contributes to the development of personalized cancer therapy for this disease

Author: Ziv Raviv, PhD

Article-7.2.2. Whole exome somatic mutations analysis of malignant melanoma contributes to the development of personalized cancer therapy for this disease

Introduction

Cutaneous melanoma is a type of skin cancer that originates in melanocytes, the cells that are producing melanin. While being the least common type of skin cancer, melanoma is the most aggressive one with invasive characteristics and accounts for the majority of death incidences among skin cancers. Melanoma has an annual rate of 160,000 new cases and 48,000 deaths worldwide. Melanoma affects mainly Caucasians exposed to sun high UV irradiation. Among the genetic factors that characterize the disease, BRAF mutation (V600E) is found in most cases of melanoma (80%).  Awareness toward risk factors of melanoma should lead to prevention and early detection*. There are several developmental stages (I-IV) of the disease, starting from local non-invasive melanoma, through invasive and high risk melanoma, up to metastatic melanoma. As with other cancers, the earlier stage melanoma is being detected, the better odds for full recovery are. Treatment is usually involving surgery to remove the local tumor and its margins, and when necessary also to remove the proximal lymph node(s) that drain the tumor. In high stages melanoma, adjuvant therapy is given in the form of chemotherapy (Dacarbazine and Temozolomide) and immunotherapy (IL-2 and IFN). Until recently no useful treatment was available for metastatic melanoma. However, research efforts had led to the development of two new drugs against metastatic melanoma: Vemurafenib (Zelboraf), a B-Raf inhibitor; and Ipilimumab (Yervoy), a monoclonal antibody that blocks the inhibitory signal of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Both drugs are now available for clinical use presenting good results.

Personalized therapy for melanoma

In an attempt to develop personalized therapies for malignant melanoma, a unique strategy has been taken by the group of Prof. Yardena Samuels at the NIH (now situated at the WIS) to identify recurring genetic alterations of metastatic cutaneous melanoma. The researchers approach employed the collections of hundreds of tumors samples taken from metastasized melanoma patients together with matched normal blood tissues samples. The samples are undergoing exome sequencing for the analysis of somatic mutations (namely mutations that evolved during the progress of the disease to the stage of metastatic melanoma, unlike genomic mutations that may have contribute to the formation of the disease). The discrimination of such tumor related somatic mutations is done by comparison to the exome sequencing of the patient’s matched blood cells DNA. In addition, the malignant cells derived from the removed cancer tissue of each patient are extracted to form a cell line and are grown in culture. These cells are easily cultivate in culture with no special media supplements, nor further genetic manipulations such as hTERT are needed, and are extremely aggressive as determined by various cell culture and in vivo tests. The ability to grow these primary tumor-derived cell lines in culture has a great value as a tool for studying and characterizing the biochemical, functional, and clinical aspects of the mutated genes identified.

In one study [1] Samuels and her colleagues performed this sequencing process for mutation analysis for the protein tyrosine kinase (PTK) gene family, as PTKs are frequently mutated in cancer. Using high-throughput gene sequencing to analyze the entire PTK gene family, the researchers have identified 30 somatic mutations affecting the kinase domains of 19 PTKs and subsequently evaluated the entire coding regions of the genes encoding these 19 PTKs for somatic mutations in 79 melanoma samples. The most frequent mutations were found in ERBB4, a member of the EGFR/ErbB family of receptor tyrosine kinase (RTK), were 19% of melanoma patients had such mutations. Seven missense mutations in the ERBB4 gene were found to induce increased kinase activity and transformation capability. Melanoma derived cell lines that were expressing these mutant ERBB4 forms had reduced cell growth after silencing ERBB4 by RNAi or after treatment with the ERBB inhibitor Lapatinib. Lapatinib is already in use in the clinic for the treatment of HER2 (ErbB2) positive breast cancers patients. Following this study, a clinical trial is now conducted with this drug to evaluate its effect in cutaneous metastatic melanoma patients harboring mutations in ERBB4.

In another study of this group [2], the scientists employed the exome sequencing method to analyze the somatic mutations of 734 G protein coupled receptors (GPCRs) in melanoma. GPCRs are regulating various signaling pathways including those that affect cell growth and play also important role in human diseases. This screen revealed that GRM3 gene that encode the metabotropic glutamate receptor 3 (mGluR3), was frequently mutated and that one of its mutations clustered within one position. Mutant GRM3 was found to selectively regulate the phosphorylation of MEK1 leading to increased anchorage-independent cell growth and cellular migration. Tumor derived melanoma cells expressing mutant GRM3 exhibited reduced cell growth and migration upon knockdown of GRM3 by RNAi or by treatment with the selective MEK inhibitor, Selumetinib (AZD-6244), a drug that is being testing in clinical trials. Altogether, the results of this study point to the increased violent characteristics of melanomas bearing mutational GRM3.

In a third study, melanoma samples were examined for somatic mutations in 19 human genes that encode ADAMTS proteins [3]. Some of the ADAMTS genes have been suggested before to have implication in tumorigenesis. ADAMTS18, which was previously found to be a candidate cancer gene, was found in this study to be highly mutated in melanoma. ADAMTS18 mutations were biologically examined and were found to induce an increased proliferation of melanoma cells, as well as increased cell migration and metastasis. Moreover, melanoma cells expressing these mutated ADAMTS18 had reduced cell migration after RNAi-mediated knockdown of ADAMTS18. Thus, these results suggest that genetic alteration of ADAMTS18 plays a major role in melanoma tumorigenesis. Since ADAMTS genes encode extracellular proteins, their accessibility to systematically delivered drugs makes them excellent therapeutic targets.

Conclusive remarks

The above illustrated research approach intends to discover frequent melanoma-specific mutations by employing high-throughput whole exome and genome sequencing means. For the most highly mutated genes identified, the biochemical, functional, and clinical aspects are being characterized to examine their relevancy to the disease outcomes. This approach therefore introduces new opportunities for clinical intervention for the treatment of cutaneous melanoma. In addition to the discovery of novel highly mutated genes, this approach may also help determine which pathways are altered in melanoma and how these genes and pathways interact. Finding melanoma-associated highly mutated genes could lead to personalized therapeutics specifically targeting these altered genes in individual melanomas. Along with the opportunity to develop new agents to treat melanoma, the approach takes advantage of existing anti-cancer drugs, utilizing them to treat these mutated genes melanoma individuals. In addition to their potential for therapeutics, the discovery of highly mutated genes in melanoma patients may lead to the discovery of new markers that may assist the diagnosis of the disease. The implications of these screenings findings on other types of cancer bearing common pathways similar to melanoma should be examined as well. Finally, this elegant approach should be adopted in research efforts of other cancer types.

* Special review will be published further in the cancer prevention section of Pharmaceutical Intelligence

References

1. Prickett TD, Agrawal NS, Wei X, Yates KE, Lin JC, Wunderlich JR, Cronin JC, Cruz P, Rosenberg SA, Samuels Y (2009) Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat Genet 41 (10):1127-1132

2. Prickett TD, Wei X, Cardenas-Navia I, Teer JK, Lin JC, Walia V, Gartner J, Jiang J, Cherukuri PF, Molinolo A, Davies MA, Gershenwald JE, Stemke-Hale K, Rosenberg SA, Margulies EH, Samuels Y (2011) Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma. Nat Genet 43 (11):1119-1126

3. Wei X, Prickett TD, Viloria CG, Molinolo A, Lin JC, Cardenas-Navia I, Cruz P, Rosenberg SA, Davies MA, Gershenwald JE, Lopez-Otin C, Samuels Y (2010) Mutational and functional analysis reveals ADAMTS18 metalloproteinase as a novel driver in melanoma. Mol Cancer Res 8 (11):1513-1525

Related articles on melanoma on this open access online scientific journal:

1.  In focus: Melanoma Genetics. Curator: Ritu Saxena, Ph.D.

2.  In focus: Melanoma therapeutics. Author and Curator: Ritu Saxena, Ph.D.

3.  A New Therapy for Melanoma.  Reporter- Larry H Bernstein, M.D.

4. Thymosin alpha1 and melanoma. Author, Editor: Tilda Barliya, Ph.D.

5. Exome sequencing of serous endometrial tumors shows recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Reporter and Curator: Dr. Sudipta Saha, Ph.D.

6. How Genome Sequencing is Revolutionizing Clinical Diagnostics. Reporter: Aviva Lev-Ari, PhD, RN.

7. Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. Curator and Reporter: Stephen J. Williams, Ph.D.

 

 

 

 

 

 

 

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In focus: Melanoma therapeutics

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Human Immune System in Health and in Disease, Molecular Genetics & Pharmaceutical, Pharmaceutical Analytics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, tagged , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , on March 8, 2013| 5 Comments »

In focus: Melanoma therapeutics

 

Author and Curator: Ritu Saxena, Ph.D.

In the last post of Melanoma titled “In focus: Melanoma Genetics”, I discussed the clinical characteristics and the genetics involved in Melanoma.  This post would discuss melanoma therapeutics, both current and novel.

According to the American Cancer Society, more than 76,000 new cases and more than 9100 deaths from melanoma were reported in the United States in 2012[1] Melanoma develops from the malignant transformation of melanocytes, the pigment-producing cells that reside in the basal epidermal layer in human skin. Although most melanomas arise in the skin, they may also arise from mucosal surfaces or at other sites to which neural crest cells migrate.

Melanoma therapeutics

Surgical treatment of cutaneous melanoma employs specific surgical margins depending on the depth of invasion of the tumor and there are specific surgical treatment guidelines of primary, nodal, and metastatic melanoma that surgeons adhere to while treatment. Melanoma researchers have been focusing on developing adjuvant therapies for that would increase the survival post-surgery.

Chemotherapy

Among traditional chemotherapeutic agents, only dacarbazine is FDA approved for the treatment of advanced melanoma (Eggermont AM and Kirkwood JM, Eur J Cancer, Aug 2004;40(12):1825-36). Dacarbazine is a triazene derivative and alkylates and cross-links DNA during all phases of the cell cycle, resulting in disruption of DNA function, cell cycle arrest, and apoptosis. Currently, 17 clinical trials are underway to test the efficacy and effectiveness of dacarbazine against melanoma as either a single agent or in combination chemotherapy regimens with other anti-cancer chemotherapeutic agents such as cisplatin, paclitaxel. Temozolomide is a triazene analog of dacarbazine and is approved for the treatment of malignant gliomas. At physiologic pH, it is converted to a short-lived active cytotoxic compound, monomethyl triazeno imidazole carboxamide (MTIC). MTIC methylates DNA at the O6 and N7 positions of guanine, resulting in inhibition of DNA replication. Unlike dacarbazine, which is metabolized to MITC only in the liver, temozolomide is metabolized to MITC at all sites. Temozolomide is administered orally and penetrates well into the central nervous system. Temozolomide is being tested in many combination regimens for patients with melanoma metastatic to the brain (Douglas JG and Margolin K, Semin Oncol, Oct 2002;29(5):518-24).

Immunotherapy

Melanoma and the immune system are closely related. Hence, immunotherapy has been explored in the treatment of the disease. The two most widely investigated immunotherapy drugs for melanoma are Interferon (IFN)-alpha and Interleukin-2 (IL-2).

The role of IFNalpha-2b in the adjuvant therapy of patients with localized melanoma at high risk for relapse was established by the results of three large randomized trials conducted by the US Intergroup; all three trials demonstrated an improvement in relapse-free survival and two in overall survival. One of these trials, a large randomized multicenter trial performed by the Eastern Cooperative Oncology Group (ECOG), in high-risk melanoma patients showed significant improvements in relapse-free and overall survival with adjuvant IFN-α-2b therapy, compared with standard observation (ECOG 1684). The results of the study led to FDA approval of IFN-α-2b for treatment of melanoma. This study was performed on patients with deep primary tumors without lymph node involvement and node-positive melanomas. In other studies, little antitumor activity has been demonstrated in IFN-α-2b–treated metastatic stage IV melanoma.

Recombinant IL-2 showed an overall response rate of 15-20% in metastatic melanoma and was capable of producing complete and durable remissions in about 6% of patients treated. Based upon these data, the US FDA has approved the use of high-dose IL-2 for the therapy of patients with metastatic melanoma. Aldesleukin (Brand name: Proleukin) is a recombinant analog of the endogenous cytokine interleukin-2 (IL-2). It binds to and activates the IL-2 receptor (IL-2R), followed by heterodimerization of the IL-2R beta and gamma(c) cytoplasmic chains; activation of Jak3; and phosphorylation of tyrosine residues on the IL-2R beta chain, resulting in an activated receptor complex (NCI). The activated complex recruits several signaling molecules that act as substrates for regulatory enzymes associated with the complex. It is administered intravenously and stimulates lymphokine-activating killer (LAK) cells, natural killer (NK) cells and the production of cytokines such as gamma interferon (nm|OK). Several clinical trials are currently underway using Aldesleukin to determine the efficacy of combination treatment in melanoma patients.

Another anti-cancer immunotherapeuty-based mechanism involved inhibition of inhibitory signal of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a molecule on T-cells that plays a critical role in regulating natural immune responses. Ipilimumab (Brand name: Yervoy) was by FDA for melanoma treatment.  It is a human monoclonal antibody (MAb) T-cell potentiator that specifically blocks CTLA-4. It is approved for inoperable advanced (Stage III) or metastatic (Stage IV) melanoma in newly diagnosed or previously treated patients (nm|OK). The approval, March 25, 2011, was based on a randomized (3:1:1) double-blind double-dummy clinical trial (MDX010-20) in patients with unresectable or metastatic melanoma who had received at least one prior systemic treatment for melanoma. Patients were randomly assigned to receive either ipilimumab, 3 mg/kg intravenously, in combination with the tumor vaccine (n=403); ipilimumab plus vaccine placebo (n=137); or tumor vaccine with placebo (n=136). Patients treated with ipilimumab alone had a median overall survival (OS) of 10 months while those treated with tumor vaccine had a median OS of 6 months. The trial also demonstrated a statistically significant improvement in OS for patients treated with the combination of ipilimumab plus tumor vaccine compared with patients treated with tumor vaccine alone. For more information on the trial, check the clinical trials website, www.clinicaltrials.gov

Signaling pathway inhibitors

Approximately 90% of BRAF gene mutations involve valine (V) to glutamic acid (E) mutation at number 600 residue (V600E). The resulting oncogene product, BRAF (V600E) kinase is highly active and exhibits elevated MAPK pathway. The BRAF(V600E) gene mutation occurs in approximately 60% of melanomas indicating that it could be therapeutically relevant. Vemurafenib (Brand name: Zelboraf) is a novel small-molecule inhibitor of BRAF (V600E) kinase. It selectively binds to the ATP-binding site and inhibits the activity of BRAF (V600E) kinase. Vemurafebib inhibits over active MAPK pathway by inhibiting the mutated BRAF kinase, thereby reducing tumor cell proliferation (NCI). Encouraging results of phase III randomized, open-label, multicenter trial were reported recently at the 2011 ASCO meeting (Chapman PB, et al, ASCO 2011, Abstract LBA4).  The trial compared the novel BRAF inhibitor vemurafenib with dacarbazine in patients with BRAF-mutated melanoma. Previously untreated, unresectable stage IIIC or stage IV melanoma that tested positive for BRAF mutation were randomized (1:1) to vemurafenib or dacarbazine. The response rate (RR) was significantly high (48.4%) in vemurafenib treated patients as compared to 5.5% in dacarbazine among the 65% of patients evaluable for RR to date. In addition, vemurafenib was associated with significantly improved OS and PFS compared to dacarbazine in patients with previously untreated BRAF (V600E) mutation bearing patients with metastatic melanoma.

Biochemotherapy

Biochemothreapy combine traditional chemotherapy with immunotherapies, such as IL-2 and IFN-α-2b. These combination therapies seemed promising in phase II trials, however, seven large studies failed to show statistically significant increased overall survival rates for various biochemotherapy regimens in patients with stage IV metastasis (Margolin KA, et al, Cancer, 1 Aug 2004;101(3):435-8). Owing to inconsistent results of the available studies with regard to benefit including RR, OS and progression time, and consistently high toxicity rates, clinical practice guideline do not recommend biochemotherapy for the treatment of metastatic melanoma (Verma S, et al, Curr Oncol, April 2008; 15(2): 85–89).

Vaccines

The use of therapeutic vaccines is an ongoing area of research, and clinical trials of several types of vaccines (whole cell, carbohydrate, peptide) are being conducted in patients with intermediate and late-stage melanoma. Vaccines are also being tested in patients with metastatic melanoma to determine their immune effects and to define their activity in combination with other immunotherapeutic agents such as IL-2 or IFNalpha (Agarwala S, Am J Clin Dermatol, 2003;4(5):333-46). In fact, recently investigators at the Indiana University Health Goshen Center for Cancer Care (Goshen, IN) conducted a randomized, multicenter phase III trial involving 185 patients with stage IV or locally advanced stage III cutaneous melanoma. The patients were assigned into treatment groups with IL-2 alone or with vaccine (gp100) followed by IL-2. The vaccine-IL-2 group had a significantly improved OR as compared to the IL-2-only group (16% Vs. 6%) and longer progression free survival (2.2 months Vs. 1.6 months). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months Vs. 11.1 months). Thus, a combination of vaccine and immunotherapy showed a better response rate and longer progression-free survival than with interleukin-2 alone in patients with advanced melanoma (Schwartzentruber DJ, et al, N Engl J Med, 2 Jun 2011;364(22):2119-27).

Which Treatment When?

Earlier, there were essentially two main options for patients suffering from advanced melanoma, dacarbazine and IL-2. Dacarbazine, a chemotherapeutic agent produces modest improvements in survival or symptomatic benefits in most patients. Interleukin-2 -based drugs, on the other hand, induce long-term remissions in a small group of patients but are highly toxic. Recently, FDA approved ipilimumab and vemurafenib for patients with metastatic melanoma. Apart from these, therapies are also aiming at starving the tumor by inhibiting angiogenesis or depleting nutrients essential for cancer growth. Of the antiangiogenic compounds, VEGFR inhibitors SU5416 and AG-013736 demonstrated broad-spectrum antitumor activity in mice bearing xenografts of human cancer cell lines originating from various tissues, including melanoma. In addition, several trials are currently underway to test the efficacy of the drugs in combination. In the future, personalized medicine-based recommendations of novel and existing drugs for melanoma patients might be the way to go.

Reference:

  1. Eggermont AM and Kirkwood JM, Eur J Cancer, Aug 2004;40(12):1825-36
  2. Douglas JG and Margolin K, Semin Oncol, Oct 2002;29(5):518-24
  3. Chapman PB, et al, ASCO 2011, Abstract LBA4
  4. Margolin KA, et al, Cancer, 1 Aug 2004;101(3):435-8
  5. Verma S, et al, Curr Oncol, April 2008; 15(2): 85–89
  6. Agarwala S, Am J Clin Dermatol, 2003;4(5):333-46
  7. Schwartzentruber DJ, et al, N Engl J Med, 2 Jun 2011;364(22):2119-27
  8. Chudnovsky Y, et al, J Clin Invest, Apr 2005;115(4):813-24.
  9. National Cancer Institute (National Institute of Health)
  10. Clinical Trials reported on the U.S. Institute of Health
  11. New Medicine Oncology KnowledgeBase (nm|OK)

Related articles on Melanoma on this Open Access Online Scientific Journal: 

  1. In focus: Melanoma Genetics Curator- Ritu Saxena, Ph.D.
  2. Thymosin alpha1 and melanoma Author/Editor- Tilda Barliya, Ph.D.
  3. A New Therapy for Melanoma  Reporter- Larry H Bernstein, M.D.
  4. Melanoma: Molecule in Immune System Could Help Treat Dangerous Skin Cancer Reporter: Prabodh Kandala, Ph.D.
  5. Why Braf inhibitors fail to treat melanoma. Reporter: Prabodh Kandala, Ph.D.

 

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In focus: Melanoma Genetics

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Genome Biology, Genomic Testing: Methodology for Diagnosis, Molecular Genetics & Pharmaceutical, tagged , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , on February 18, 2013| 4 Comments »

Curator: Ritu Saxena, Ph.D.

Melanoma

Melanoma represents approximately 4% of human skin cancers, yet accounts for approximately 80% of deaths from cutaneous neoplasms. It remains one of the most common types of cancer among young adults. Melanoma is recognized as the most common fatal skin cancer with its incidence rising to 15 fold in the past 40 years in the United States. Melanoma develops from the malignant transformation of melanocytes, the pigment-producing cells that reside in the basal epidermal layer in human skin. (Greenlee RT, et al, Cancer J Clin. Jan-Feb 2001;51(1):15-36 ; Weinstock MA, et al, Med Health R I. Jul 2001;84(7):234-6).  Classic clinical signs of melanoma include change in color, recent enlargement, nodularity, irregular borders, and bleeding. Cardinal signs of melanoma are sometimes referred to by the mnemonic ABCDEs (asymmetry, border irregularity, color, diameter, elevation) (Chudnovsky Y, et al. J Clin Invest, 1 April 2005; 115(4): 813–824).

Clinical characteristics

Melanoma primarily affects fair-haired and fair-skinned individuals, and those who burn easily or have a history of severe sunburn are at higher risk than their darkly pigmented, age-matched controls. The exact mechanism and wavelengths of UV light that are the most critical remain controversial, but both UV-A (wavelength 320–400 nm) and UV-B (290–320 nm) have been implicated (Jhappan C, et al, Oncogene, 19 May 2003;22(20):3099-112). Case-control studies have identified several risk factors in populations susceptible to developing melanoma. MacKie RM et al (1989) stated that the relative risk of cutaneous melanoma is estimated from the four strongest risk factors identified by conditional logistic regression. These factors are

  • total number of benign pigmented naevi above 2 mm diameter;
  • freckling tendency;
  • number of clinically atypical naevi (over 5 mm diameter and having an irregular edge, irregular pigmentation, or inflammation); and
  • a history of severe sunburn at any time in life.

Use of this risk-factor chart should enable preventive advice for and surveillance of those at greatest risk (MacKie RM, et al, Lancet 26 Aug1989;2(8661):487-90).

Cutaneous melanoma can be subdivided into several subtypes, primarily based on anatomic location and patterns of growth (Table 1).

Image

Table 1: Clinical Classification of Melanoma (Chudnovsky Y, et al, 2005)

The genetics of melanoma

As in many cancers, both genetic predisposition and exposure to environmental agents are risk factors for melanoma development. Many studies conducted over several decades on benign and malignant melanocytic lesions as well as melanoma cell lines have implicated numerous genes in melanoma development and progression.

Image

Table 2: Genes involved in Melanoma (Chudnovsky Y, et al, 2005)

Apart from the risk factors such as skin pigmentation, freckling, and so on, another significant risk factor is ‘strong family history of melanoma’. Older case-control studies of patients with familial atypical mole-melanoma (FAMM) syndrome suggested an elevated risk of ∼434-to 1000-fold over the general population (Greene MH, et al, Ann Intern Med, Apr 1985;102(4):458-65). A more recent meta-analysis of family history found that the presence of at least one first-degree relative with melanoma increases the risk by 2.24-fold (Gandini S, et al, Eur J Cancer, Sep 2005;41(14):2040-59). Genetic studies of melanoma-prone families have given important clues regarding melanoma susceptibility loci.

CDKN2A, the familial melanoma locus

CDKN2A is located at chromosome 9p21 and is composed of 4 exons (E) – 1α, 1β, 2, and 3. LOH or mutations at this locus cosegregated with melanoma susceptibility in familial melanoma kindred and 9p21 mutations have been observed in different cancer cell lines. The locus encodes two tumor suppressors via alternate reading frames, INK4 (p16INK4a) and ARF (p14ARF). INK4A and ARF encode alternative first exons, 1α and 1β respectively and different promoters. INK4A is translated from the splice product of E1α, E2, and E3, while ARF is translated from the splice product of E1β, E2, and E3. Second exons of the two proteins are shared and two translated proteins share no amino acid homology.

INK4A is the founding member of the INK4 (Inhibitor of cyclin-dependent kinase 4) family of proteins and inhibits the G1 cyclin-dependent kinases (CDKs) 4/6, which phosphorylate and inactivate the retinoblastoma protein (RB), thereby allowing for S-phase entry. Thus, loss of INK4K function promotes RB inactivation through hyperphosphorylation, resulting in unconstrained cell cycle progression.

ARF (Alternative Reading Frame) protein of the locus inhibits HDM2-mediated ubiquitination and subsequent degradation of p53. Thus, loss of ARF inactivates another tumor suppressor, p53. The loss of p53 impairs mechanisms that normally target genetically damaged cells for cell cycle arrest and/or apoptosis, which leads to proliferation of damaged cells. Loss of CDKN2A therefore contributes to tumorigenesis by disruption of both the pRB and p53 pathways.

figure 1

Figure 1:  Genetic encoding and mechanism of action of INK4A and ARF.

(Chudnovsky Y, et al, 2005)

RAF and RAS pathways

A genetic hallmark of melanoma is the presence of activating mutations in the oncogenes BRAF and NRAS, which are present in 70% and 15% of melanomas, respectively, and lead to constitutive activation of mitogen-activated protein kinase (MAPK) pathway signaling. However, molecules that inhibit MAPK pathway–associated kinases, like BRAF and MEK, have shown only limited efficacy in the treatment of metastatic melanoma. Thus, a deeper understanding of the cross talk between signaling networks and the complexity of melanoma progression should lead to more effective therapy.

NRAS mutations activate both effector pathways, Raf-MEK-ERK and PI3K-Akt in melanoma. The Raf-MEK-ERK pathway may also be activated via mutations in the BRAF gene. In a subset of melanomas, the ERK kinases have been shown to be constitutively active even in the absence of NRAS or BRAF mutations. The PI3K-Akt pathway may be activated through loss or mutation of the tumor suppressor gene PTEN, occurring in 30–50% of melanomas, or through gene amplification of the AKT3 isoform. Activation of ERK and/or Akt3 promotes the development of melanoma by various mechanisms, including stimulation of cell proliferation and enhanced resistance to apoptosis.

JCI0524808.f3

Figure 2: Schematic of the canonical Ras effector pathways Raf-MEK-ERK and PI3K-Akt in melanoma.

Curtin et al (2005) compared genome-wide alterations in the number of copies of DNA and mutational status of BRAF and NRAS in 126 melanomas from four groups in which the degree of exposure to ultraviolet light differs: 30 melanomas from skin with chronic sun-induced damage and 40 melanomas from skin without such damage; 36 melanomas from palms, soles, and subungual (acral) sites; and 20 mucosal melanomas. Significant differences were observed in number of copies of DNA and mutation frequencies in BRAF among the four groups of melanomas. Eighty-one percent of the melanomas on skin without sun-induced damaged had mutations in BRAF or NRAS. Melanomas with wild-type BRAF or NRAS frequently had increases in the number of copies of the genes for cyclin-dependent kinase 4 (CDK4) and cyclin D1 (CCND1), downstream components of the RAS-BRAF pathway. Thus, the genetic alterations identified in melanomas at different sites and with different levels of sun exposure indicate that there are distinct genetic pathways in the development of melanoma and implicate CDK4 and CCND1 as independent oncogenes in melanomas without mutations in BRAF or NRAS. (Curtin JA, et al, N Engl J Med, 17 Nov 2005;353(20):2135-47).

Genetic Heterogeneity of Melanoma

Melanoma exhibits molecular heterogeneity with markedly distinct biological and clinical behaviors. Lentigo maligna melanomas, for example, are indolent tumors that develop over decades on chronically sun-exposed area such as the face. Acral lentigenous melanoma, or the other hand, develops on sun-protected regions, tend to be more aggressive. Also, transcription profiling has provided distinct molecular subclasses of melanoma. It is also speculated that alterations at the DNA and RNA and the non-random nature of chromosomal aberrations may segregate melanoma tumors into subtypes with distinct clinical behaviors.

The melanoma gene atlas

Whole-genome screening technologies such as spectral karyotype analysis and array-CGH have identified many recurrent nonrandom chromosomal structural alterations, particularly in chromosomes 1, 6, 7, 9, 10, and 11 (Curtin JA, et al, N Engl J Med, 17 Nov 2005;353(20):2135-47); however, in most cases, no known or validated targets have been linked to these alterations.

In A systematic high-resolution genomic analysis of melanocytic genomes, array-CGH profiles of 120 melanocytic lesions, including 32 melanoma cell lines, 10 benign melanocytic nevi, and 78 melanomas (primary and metastatic) by Chin et al (2006) revealed a level of genomic complexity not previously appreciated. In total, 435 distinct copy number aberrations (CNAs) were defined among the metastatic lesions, including 163 recurrent, high-amplitude events. These include all previously described large and focal events (e.g., 1q gain, 6p gain/6q loss, 7 gain, 9p loss, and 10 loss). Genomic complexity observed in primary and benign nevi melanoma is significantly less than that observed in metastatic melanoma (Figure 3)  (Chin L, et al, Genes Dev. 15 Aug 2006;20 (16):2149-2182).

Genetic heterogeneity Melanoma

Figure 3: Genome comparisons of melanocyte lesions (Chin L, et al, 2006)

Thus, genomic profiling of various melanoma progression types could reveal important information regarding genetic events those likely drive as metastasis and possibly, reveal provide cues regarding therapy targeted against melanoma.

Reference:

  1. Greenlee RT, et al, Cancer J Clin. Jan-Feb 2001;51(1):15-36
  2. Weinstock MA, et al, Med Health R I. Jul 2001;84(7):234-6
  3. Chudnovsky Y, et al. J Clin Invest, 1 April 2005; 115(4): 813–824
  4. Jhappan C, et al, Oncogene, 19 May 2003;22(20):3099-112
  5. MacKie RM, et al, Lancet 26 Aug1989;2(8661):487-90)
  6. Gandini S, et al, Eur J Cancer, Sep 2005;41(14):2040-59)
  7. Curtin JA, et al, N Engl J Med, 17 Nov 2005;353(20):2135-47
  8. Chin L, et al, Genes Dev. 15 Aug 2006;20 (16):2149-2182

Related articles on Melanoma on this Open Access Online Scientific Journal, include the following: 

Thymosin alpha1 and melanoma Author/Editor- Tilda Barliya, Ph.D.

A New Therapy for Melanoma Reporter- Larry H Bernstein, M.D.

Melanoma: Molecule in Immune System Could Help Treat Dangerous Skin Cancer Reporter: Prabodh Kandala, Ph.D.

Why Braf inhibitors fail to treat melanoma. Reporter: Prabodh Kandala, Ph.D.

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“Thymosin alpha1 and melanoma”

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, tagged , , , , , , , , , , on February 15, 2013| 2 Comments »

Author, Editor: Tilda Barliya, PhD

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Although melanoma accounts for only 4 percent of all dermatologic cancers, it is responsible for 80 percent of deaths from skin cancer; only 14 percent of patients with metastatic melanoma survive for five years (1). The incidence of melanoma is increasing worldwide, with a growing fraction of patients with advanced disease for which prognosis remains poor despite advances in the field (2). Treatment options are limited despite advances in immunotherapy and targeted therapy. For patients with surgically resected, thick (≥2 mm) primary melanoma with or without regional lymph node metastases, the only effective adjuvant therapy is interferon-α (IFN-α). However, because of the limited benefit upon disease-free survival and the smaller potential improvement of overall survival, the indication for IFN-α treatment remains controversial (2). A better understanding of melanoma immunosurveillance is therefore essential to enable the design of better, targeted melanoma therapies (4).

Risk factors (2):

  • Family history of melanoma, multiple benign or atypical nevi, and a previous melanoma
  • Immunosuppression
  • Sun sensitivity
  • Exposure to ultraviolet radiation

Each of these risk factors corresponds to a genetic predisposition or an environmental stressor that contributes to the genesis of melanoma and each factor is understood to various degrees at a molecular level. The Clark model of the progression of melanoma emphasizes the stepwise transformation of melanocytes to melanoma. The model depicts the proliferation of melanocytes in the process of forming nevi and the subsequent development of dysplasia, hyperplasia, invasion, and metastasis.

 

This Clark’s multi-step model, and predict that the acquisition of a BRAF mutation can be a founder event in melanocytic neoplasia. While mutations of the BRAF gene are frequent in melanomas on non-chronic sun damaged skin which are prevalent in Caucasians, acral and mucosal melanomas harbor mutations of the KIT gene as well as the amplifications of cyclin D1 or cyclin-dependent kinase 4 gene.

The choice of target antigens is key to the success of tumour vaccination or tumour immunotherapy. Melanoma candidate antigens include: (A) mutated or aberrantly expressed molecules (e.g. CDK4, MUM-1, beta-catenin) (B) cancer/testis antigens (e.g. MAGE, BAGE and GAGE) and (C) melanoma- associated antigens (MAA).

MAAs are self-antigens normally expressed during the differentiation of melanocytes and play a role in different enzymatic steps of melanogenesis. However, in transformed melanocytes (melanoma cells), MAAs are often overexpressed (4).

The main MAAs are tyrosinase, an enzyme that catalyses the production of melanin from tyrosine by oxidation, the tyrosinase-related proteins (TRP-1) and 2 (TRP-2), the glycoprotein (gp)100 (silver-gene) and MelanA/MART. It is thought that the specialized cell biology of melanin synthesis may favour the loading of MAA peptides into the antigen presentation pathway. 50% of melanoma patients have tumour-infiltrating lymphocytes (TILs) recognising tyrosinase and Melan A, indicating that these antigens are important in the natural melanoma immunosurveillance. Moreover, MAAs are well characterized in mice and humans, allowing the development of tetramers to detect antigen-specific immune responses.

Tα1 Mechanism of action

Tα1, a 28 amino acid peptide of ∼3.1 kDa, is endogenously produced by the thymus gland by the cleavage of its precursor pro-Ta1.  Although the fine immunologic mechanism(s) of action of T1 have not fully been elucidated, experimental evidence points to its strong immunomodulatory properties. In particular, it was reported that Ta1 enhances T cell–mediated immune responses by several mechanisms, including increased T cell production (i.e., CD4+, CD8+, and CD3+ cells), stimulation of T cell differentiation and/or maturation, reduction of T cell apoptosis, and restoration of T cell–mediated antibody production (5).

Furthermore, it was demonstrated that T1 acts on the immune system by modulating the release of proinflammatory cytokines (i.e., interleukin-2 (IL-2), interferon-gamma (IFN-)),12–14 and through the activation of natural killer and dendritic cells.12 In addition, T1 was also demonstrated to have direct effects on cancer cells by increasing the levels of expression of different tumor antigens and of components of the major histocompatibility complex class I, as well as by reducing cancer cell growth.

Together, these experimental findings bear relevance for cancer immunotherapy and suggest that T1 can activate innate and adaptive immune responses and modulate the immunophenotype of cancer cells, improving their immunogenicity and their recognition by the immune system.

Danielli R and colleagues have very nicely outlined the use of the Thymosin a1 in the clinical setting for treating melanoma (5) titled :”Thymosin a1 in melanoma: from the clinical trial setting to the daily practice and beyond”.  A large body of available preclinical in vitro and in vivo evidence points to thymosin alpha 1 (Ta1) as a useful immunomodulatory peptide,with significant therapeutic potential in metastatic melanoma in the absence of clinically meaningful toxicity.  The results emerging frominitial trials provide support of the ability of T1 to improve the clinical outcome of advanced melanoma patients through the activation of the immune system.

Ta1 and Clinical Trials in Melanoma

A large scale, randomized, phase II study was conducted at 64 European centers between 2002 and 2006 to investigate the efficacy of Ta1 administered in combination with DTIC (Dacarbazine) or with DTIC + IFNa, versus only DTIC + IFNa, in 488 previously untreated patients with cutaneous metastatic melanoma. The study was designed to evaluate the ability of Ta1 to potentiate the therapeutic efficacy of DTIC.

Patients were randomly assigned to five treatment groups: DTIC + IFNa and 1.6 mg of Ta1; DTIC + IFNa and 3.2 mg of T1; DTIC + IFN-a and 6.4 mg of Ta1; DTIC + 3.2 mg of Ta1; and DTIC + IFNa

Results:

The clinical rate (CBR), defined as the proportion of patients with a complete response, partial response, or stable disease, was significantly higher in patients who received Ta1 + DTIC than in those who received control therapy. Results in patients who received T1 (all groups combined) compared with those who received the control treatment

  • Improved progression-free survival (hazard ratio (HR): 0.80;
  • 95%confidence interval (CI): 0.63–1.01; P = 0.06) and
  • OS (median: 9.4 vs. 6.6 months)

These outcomes suggested to addition of Thymosin a1 to the treatment resulted in the reduction in the risk of mortality and disease progression in patients with metastatic malignant melanoma, and pointed to a poor effect of IFN- in the combination. More so, the poor results of the IFN group is not surprising due to the limited therapeutic activity of IFN observed in phase III clinical trials.

This study however have some limitations as standard assessment criteria, such as RECIST and WHO indications,  conventionally applied to cytotoxic agents, do not adequately capture some patterns of response observed in the course of immunotherapy; stemming from these considerations, immune-related response criteria (irRC) were developed to measure primary and secondary endpoints in immunotherapy clinical trials.

Therefore the above study might underestimate the therapeutic efficacy of Thymosin a1 since irRC criteria were not used.

In Summary:

A large scale phase III clinical trial should be designed to further explore the therapeutic activity of Thymosine a1 in melanoma patients with defined endpoints and irRC criteria. Moreover, combination studies should explore the activity of T1 in association with other approved agents, such as ipilimumab and vemurafenib or as maintenance therapy in melanoma patients who experience clinical benefit after treatment with these agents.

Also, because of the pleiotropic immunemechanism(s) of action of T1, including the upregulation of T cell–driven immune responses against specific tumor antigens, priming of immune responses and potentiation of antitumor T cell–mediated immune responses through the activation of Toll-like receptor 9 on dendritic cells, coupling Ta1 to cancer vaccines should be an additional useful therapeutic strategy to pursue. T1 could, in fact, prove helpful in overcoming the limited immunogenicity and the short-lived persistency of adequate immunologic antitumor responses frequently reported as potential causes of failure of therapeutic vaccines.

Ref:

1. Arlo J. Miller, M.D.,., and Martin C. Mihm, Jr. Mechanisms of disease: Melanoma. N Engl J Med 2006 (6); 355:51-65.

http://www.nejm.org.rproxy.tau.ac.il/doi/pdf/10.1056/NEJMra052166

http://www.nejm.org/doi/full/10.1056/NEJMra052166

2. Garbe C., Eigentler TK., Keilholz U., Hauschild A and Kirkwood JM. Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist 2011;16(1):5-24.

http://theoncologist.alphamedpress.org/content/16/1/5.long

3. http://flipper.diff.org/app/items/info/1983

4.  Träger U, Sierro S, Djordjevic G, Bouzo B, Khandwala S, et al. (2012) The Immune Response to Melanoma Is Limited by Thymic Selection of Self-Antigens. PLoS ONE 7(4): e35005. doi:10.1371/journal.pone.0035005.

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035005

5. Riccardo Danielli, Ester Fonsatti, Luana Calabr` o, Anna Maria Di Giacomo, and Michele Maio. Thymosin 1 in melanoma: from the clinical trial setting to the daily practice and beyond. Ann. N.Y. Acad. Sci. 1270 (2012) 8–12.

http://www.ncbi.nlm.nih.gov/pubmed/16822996

http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2012.06757.x/abstract

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Rewriting the Mathematics of Tumor Growth; Teams Use Math Models to Sort Drivers from Passengers

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Interviews with Scientific Leaders, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Statistical Methods for Research Evaluation, tagged , , , , , , , , , , , , , , , , , , , , , , , , , on February 10, 2013| Leave a Comment »

Rewriting the Mathematics of Tumor Growth[1]; Teams Use Math Models to Sort Drivers from Passengers[2]:  Two JNCI Reviews by Mike Martin Regarding Genomics, Cancer, and Mutation

Curator: Stephen J. Williams, Ph.D.

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Recently, there has been extensive interest in the cancer research and oncology community on detecting those mutations responsible for the initiation and propagation of a neoplastic cell (driver mutations) versus those mutations that are randomly (or by selective pressures) acquired due to the genetic instability of the transformed cell.  The impact of either type of mutation has been a topic for debate, with a recent article showing that some passenger mutations may actually be responsible for tumor survival.  In addition many articles, highlighted on this site (and referenced below) in recent years have described the importance of classifying driver and passenger mutations for the purposes of more effective personalized medicine strategies directed against tumors. Two review articles by Mike Martin in the Journal of the National Cancer Institute (JCNI) shed light on the current efforts and successes to discriminate between these passenger and driver mutations and determine impact of each type of mutation to tumor growth.  However, as described in the associated article, the picture is not as clear cut as previously thought and highlights some revolutionary findings. In Rewriting the Mathematics of Tumor Growth, researchers discovered that driver mutations may confer such a small growth advantage that, multiple mutations, including the so called passenger mutations are necessary in order to sustain tumor growth. In fact, much experimental evidence has suggested at least six defined genetic events may be necessary for the in-vitro transformation of human cells.  The following table shows some of the genetic events required for in-vitro transformation in cell culture systems.

Genetic events required for transformation

 Species  Cell type  # of genes required for tumor formation*  Genes used  Reference Events required for priming
Human FibroblastsEmbryonic kidney 3 hTERTH-rasLarge T (a)Hahn(Weinberg) 2LT+hTERT
Mammary epithelialMyoblastsEmbryonic kidney 6 hTERTH-rasP53DDc-myccyclin D1CDK4 (b)Kendall(Counter) Hras required for tumorigenesis so probably 5 events needed
Fibroblasts 4 Large TSmall TH-rashTERT (c)Sun(Hornsby) 2Large T + H-ras
Fibroblasts 4 Large TSmall ThTERTRas (d)Rangarajan(Weinberg) 3hTERT, Ras and either small or largeT
Keratinocytes 4 CyclinD1dnp53EGFR

c-myc

 (e)Goessel(Opitz) 3 for anchorage independence (cyclin D1, dnp53, EGFR),Cyclin D1+dnp53 for immortalization
HOSE 6 CDK4, cyclin D, hTERT plus combination of either P53DD, myrAkt, and H-ras or P53DD, H-ras, c-myc Bcl2 (f)Sasaki(Kiyono) 5
HOSE 3 hTERTSV40 earlyH-ras orK-ras (g)Liu(Bast) 2hTERT+ SV40 early
HOSE 3 Large ThTERTH-ras orc-erB-2 (h)Kusakari(Fujii) 2hTERT+large T
Rat Fibroblasts 2 Large TH-ras (i)Hirakawa Did not analyze
Fibroblasts 2 Large TH-ras (d)Rangarajan(Weinberg) Large T
Mouse MOSEIn p53-/- background 3 c-mycK-rasAkt (j)Orsulic
Pig Fibroblasts 6 p53DDhTERTCDK4H-ras c-myccyclin D1 (k)Adam(Counter) 5 need all butp53DD

Note: priming means events required to immortalize but not fully transform.  * Note that both ability to form colonies in soft agarose and subsequently tested for tumor formation in immunocompromised mice.

a.         Hahn, W. C., Counter, C. M., Lundberg, A. S., Beijersbergen, R. L., Brooks, M. W., and Weinberg, R. A. (1999) Creation of human tumour cells with defined genetic elements, Nature 400, 464-468.

b.         Kendall, S. D., Linardic, C. M., Adam, S. J., and Counter, C. M. (2005) A network of genetic events sufficient to convert normal human cells to a tumorigenic state, Cancer Res 65, 9824-9828.

c.         Sun, B., Chen, M., Hawks, C. L., Pereira-Smith, O. M., and Hornsby, P. J. (2005) The minimal set of genetic alterations required for conversion of primary human fibroblasts to cancer cells in the subrenal capsule assay, Neoplasia 7, 585-593.

d.         Rangarajan, A., Hong, S. J., Gifford, A., and Weinberg, R. A. (2004) Species- and cell type-specific requirements for cellular transformation, Cancer Cell 6, 171-183.

e.         Goessel, G., Quante, M., Hahn, W. C., Harada, H., Heeg, S., Suliman, Y., Doebele, M., von Werder, A., Fulda, C., Nakagawa, H., Rustgi, A. K., Blum, H. E., and Opitz, O. G. (2005) Creating oral squamous cancer cells: a cellular model of oral-esophageal carcinogenesis, Proc Natl Acad Sci U S A 102, 15599-15604.

f.          Sasaki, R., Narisawa-Saito, M., Yugawa, T., Fujita, M., Tashiro, H., Katabuchi, H., and Kiyono, T. (2009) Oncogenic transformation of human ovarian surface epithelial cells with defined cellular oncogenes, Carcinogenesis 30, 423-431.

g.         Liu, J., Yang, G., Thompson-Lanza, J. A., Glassman, A., Hayes, K., Patterson, A., Marquez, R. T., Auersperg, N., Yu, Y., Hahn, W. C., Mills, G. B., and Bast, R. C., Jr. (2004) A genetically defined model for human ovarian cancer, Cancer Res 64, 1655-1663.

h.         Kusakari, T., Kariya, M., Mandai, M., Tsuruta, Y., Hamid, A. A., Fukuhara, K., Nanbu, K., Takakura, K., and Fujii, S. (2003) C-erbB-2 or mutant Ha-ras induced malignant transformation of immortalized human ovarian surface epithelial cells in vitro, Br J Cancer 89, 2293-2298.

i.          Hirakawa, T., and Ruley, H. E. (1988) Rescue of cells from ras oncogene-induced growth arrest by a second, complementing, oncogene, Proc Natl Acad Sci U S A 85, 1519-1523.

j.          Orsulic, S., Li, Y., Soslow, R. A., Vitale-Cross, L. A., Gutkind, J. S., and Varmus, H. E. (2002) Induction of ovarian cancer by defined multiple genetic changes in a mouse model system, Cancer Cell 1, 53-62.

k.         Adam, S. J., Rund, L. A., Kuzmuk, K. N., Zachary, J. F., Schook, L. B., and Counter, C. M. (2007) Genetic induction of tumorigenesis in swine, Oncogene 26, 1038-1045.

However it may be argued that the aforementioned experimental examples were produced in cell lines with a more stable genome than that which is seen in most tumors and had used traditional assays of transformation, such as growth in soft agarose and tumorigenicity in immunocompromised mice, as endpoints of transformation, and not representative of the tumor growth seen in the clinical setting.

Therefore Bert Vogelstein, M.D., along with collaborators around the world developed a model they termed the “sequential driver mutation theory”, in which they describe that driver mutations multiply over time with each mutation “slightly increasing the tumor growth rate through a process that depends on three factors”:

  1. Driver mutation rate
  2. The 0.4% selective growth advantage
  3. Cell division time

This model was based on a combination of experimental data and computer simulations of gliobastoma multiforme and pancreatic adenocarcinoma.  Most tumor models follow a Gompertz kinetics, which show how tumor growth is exponential but eventually levels off over time.

This new theory shows though that a tumor cell with only one driver mutation can only grow so much, until a second driver mutation is required.  Using data for the COSMIC database (Catalog of Somatic Mutations in Cancer) together with analysis software CHASM (Cancer-specific High-throughput Annotation of Somatic Mutations) the researchers analyzed 713 mutations sequenced from 14 glioma patients and 562 mutations in nine pancreatic adenocarcinomas, revealing at least 100 tumor suppressor genes and 100 oncogenes altered.  Therefore, the authors suggested these may be possible driver mutations, or at least mutations required for the sustained growth of these tumors.  Applying this new model to data obtained from Dr. Giardiello’s publication concerning familial adenopolypsis in New England Journal of medicine in 19993 and 2000, the sequential driver mutation model predicted age distribution of FAP patients, number and size of polyps, and polyp growth rate than previous models.  This surprising number of required driver mutations for full transformation was also verified in a study led by University of Texas Southwestern Medical Center biologist Jerry Shay, Ph.D., who noted “this team’s surprise nearly 45% of all colorectal candidate oncogenes (65 mutations) drove malignant proliferation”[3].

However, some investigators do not believe the model is complex enough to account for other factors involved in oncogenesis, such as epigenetic factors like methylation and acetylation.  In addition the review also discusses host and tissue factors which may complicate the models, such as location where a tumor develops.  However, most of the investigators interviewed for this review agreed that focusing on this long-term progression of the disease may give us clues to other potential druggable targets.

Teams Use Math Models to Sort Drivers From Passengers

A related review from Mike Martin in JNCI [2] describes a statistical method, published in 2009 Cancer Informatics[4], which distinguishes chromosomal abnormalities that can drive oncogenesis from passenger abnormalities.  Chromosomal abnormalities, such as deletions, additions, and translocations are common in cancer.  For instance, the well-known Philadelphia chromosome, a translocation between chromosome 9 and 22 which results in the BCR-ABL tyrosine kinase fusion protein is the molecular basis of chronic myelogenous leukemia.

In the report, Eytan Domany, Ph.D., from Weizmann Institute and several colleagues from University of Lausanne, University of Haifa and the Broad Institute were analyzing chromosomal aberrations in a subset of medulloblastoma, which had more gain and losses in chromosomes than had been attributed to the disease.  Using a statistical method they termed a “volumetric sieve”, the investigators were able to identify driver versus passenger aberrations based on three filters:

  • Fraction of patients with the abnormality
  • Length of DNA involved in the aberrant chromosome
  • Abnormality’s copy number

Another method to sort the most “important” chromosomal aberrations from less relevant alterations is termed GISTIC[5], as the website describes is: a tool to identify genes targeted by somatic copy-number alterations (SCNAs) that drive cancer growth (at the Broad Institute website http://www.broadinstitute.org/software/cprg/?q=node/31).  The method allows for comparison across multiple tumors so noise is eliminated and improves consistency of analysis.  This method had been successfully used to determine driver aberrations is mesotheliomas, leukemias, and identify new oncogenes in adenocarcinomas of the lung and squamous cell carcinoma of the esophagus.

Main references for the two Mike Martin articles are as follows:

1.         Martin M: Rewriting the mathematics of tumor growth. Journal of the National Cancer Institute 2011, 103(21):1564-1565.

2.         Martin M: Aberrant chromosomes: teams use math models to sort drivers from passengers. Journal of the National Cancer Institute 2010, 102(6):369-371.

3.         Eskiocak U, Kim SB, Ly P, Roig AI, Biglione S, Komurov K, Cornelius C, Wright WE, White MA, Shay JW: Functional parsing of driver mutations in the colorectal cancer genome reveals numerous suppressors of anchorage-independent growth. Cancer research 2011, 71(13):4359-4365.

4.         Shay T, Lambiv WL, Reiner-Benaim A, Hegi ME, Domany E: Combining chromosomal arm status and significantly aberrant genomic locations reveals new cancer subtypes. Cancer informatics 2009, 7:91-104.

5.         Beroukhim R, Getz G, Nghiemphu L, Barretina J, Hsueh T, Linhart D, Vivanco I, Lee JC, Huang JH, Alexander S et al: Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proceedings of the National Academy of Sciences of the United States of America 2007, 104(50):20007-20012.

Further posts on CANCER and GENOMICS and Sequencing published on the site include:

The Initiation and Growth of Molecular Biology and Genomics

Inaugural Genomics in Medicine – The Conference Program, 2/11-12/2013, San Francisco, CA

LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment: Part 2

Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1

Breast Cancer: Genomic profiling to predict Survival: Combination of Histopathology and Gene Expression Analysis

Computational Genomics Center: New Unification of Computational Technologies at Stanford

GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial”

arrayMap: Genomic Feature Mining of Cancer Entities of Copy Number Abnormalities (CNAs) Data

Comprehensive Genomic Characterization of Squamous Cell Lung Cancers

Mosaicism’ is Associated with Aging and Chronic Diseases like Cancer: detection of genetic mosaicism could be an early marker for detecting cancer.

http://onlinelibrary.wiley.com/doi/10.1111/j.1755-148X.2011.00905.x/full

http://pharmaceuticalintelligence.com/2013/02/05/winning-over-cancer-progression-new-oncology-drugs-to-suppress-driver-mutations-vs-passengers-mutations/

Additional references:

[1] Michor F, Iwasa Y, and Nowak MA (2004) Dynamics of cancer

progression. Nature Reviews Cancer 4, 197-205.

[2] Crespi B and Summers K (2005) Evolutionary biology of cancer.

Trends in Ecology and Evolution 20, 545-552.

[3] Merlo LMF, et al. (2006) Cancer as an evolutionary and ecological

process. Nature Reviews Cancer 6, 924-935.

[4] McFarland C, et al. “Accumulation of deleterious passenger mutations

in cancer,” in preparation.

[5] Birkbak NJ, et al. (2011) Paradoxical relationship between

chromosomal instability and survival outcome in cancer. Cancer

Research 71,3447-3452.

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Reboot evidence-based medicine and reconsider the randomized, placebo-controlled clinical trial

Posted in Computational Biology/Systems and Bioinformatics, FDA Regulatory Affairs, Genome Biology, Health Economics and Outcomes Research, Health Law & Patient Safety, HealthCare IT, Medical Devices R&D Investment, Personalized and Precision Medicine & Genomic Research, Proteomics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, tagged , , , , , , , on November 4, 2012| 5 Comments »

Larry H Bernstein, MD, FACP, Reporter

Clinical Trials
Dr. Eric Topol, Director of the Scripps Translational Science Institute and Editor-in-Chief of Medscape Genomic Medicine and the heart.org.
In our series The Creative Destruction of Medicine, I’m trying to get into critical aspects of how we can Schumpeter or reboot the future of healthcare by leveraging the big innovations that are occurring in the digital world, including digital medicine.

But one of the things that has been missed along the way is that how we do clinical research will be radically affected as well. We have this big thing about evidence-based medicine and, of course, the sanctimonious randomized, placebo-controlled clinical trial. Well, that’s great if one can do that, but often we’re talking about needing thousands, if not tens of thousands, of patients for these types of clinical trials. And things are changing so fast with respect to medicine and, for example, genomically guided interventions that it’s going to become increasingly difficult to justify these very large clinical trials.

For example, there was a drug trial for melanoma and the mutation of BRAF, which is the gene that is found in about 60% of people with malignant melanoma. When that trial was done, there was a placebo control, and there was a big ethical charge asking whether it is justifiable to have a body count. This was a matched drug for the biology underpinning metastatic melanoma, which is essentially a fatal condition within 1 year, and researchers were giving some individuals a placebo.

Would we even do that kind of trial in the future when we now have such elegant matching of the biological defect and the specific drug intervention? A remarkable example of a trial of the future was announced in May.[1] For this trial, the National Institutes of Health is working with [Banner Alzheimer’s Institute] in Arizona, the University of Antioquia in Colombia, and Genentech to have a specific mutation studied in a large extended family living in the country of Colombia in South America. There is a family of 8000 individuals who have the so-called Paisa mutation, a presenilin gene mutation, which results in every member of this family developing dementia in their 40s.

Clinical Trials (journal)

Clinical Trials (journal) (Photo credit: Wikipedia)

Related articles

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Melanoma: Molecule in Immune System Could Help Treat Dangerous Skin Cancer

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, tagged , , , , on July 8, 2012| 2 Comments »

Reporter: Prabodh Kandala, PhD.

Researchers from Brigham and Women’s Hospital (BWH) have made a groundbreaking discovery that will shape the future of melanoma therapy. The team, led by Thomas S. Kupper, MD, chair of the BWH Department of Dermatology, and Rahul Purwar, PhD, found that high expression of a cell-signaling molecule, known as interleukin-9, in immune cells inhibits melanoma growth.

After observing mice without genes responsible for development of an immune cell called T helper cell 17 (TH17), researchers found that these mice had significant resistance to melanoma tumor growth, suggesting that blockade of the TH17 cell pathway favored tumor inhibition. The researchers also noticed that the mice expressed high amounts of interleukin-9.

“These were unexpected results, which led us to examine a possible contribution of interleukin-9 to cancer growth suppression.” said Purwar.

The researchers next treated melanoma-bearing mice with T helper cell 9 (TH9), an immune cell that produces interleukin-9. They saw that these mice also had a profound resistance to melanoma growth. This is the first reported finding showing an anti-tumor effect of TH9 cells.

Moreover, the researchers were able to detect TH9 cells in both normal human blood and skin, specifically in skin-resident memory T cells and memory T cells in peripheral blood mononuclear cells. In contrast, TH9 cells were either absent or present at very low levels in human melanoma. This new finding paves the way for future studies that will assess the role of interleukin-9 and TH9 cells in human cancer therapy.

“Immunotherapy of cancer is coming of age, and there have been exciting recent results in patients with melanoma treated with drugs that stimulate the immune system,” said Kupper. “We hope that our results will also translate to the treatment of melanoma patients, but much work still needs to be done.”

According to the researchers, other cell-signaling molecules have been used in treating melanoma; however, this study is the first to investigate the role of interleukin-9 in melanoma tumor immunity.

Melanoma is the most dangerous form of skin cancer. The National Cancer Institute estimates that in 2012, there will be more than 76,000 new cases of melanoma in the United States and 9,180 deaths. Melanoma is curable if recognized and treated early.

Abstract:

Interleukin-9 (IL-9) is a T cell cytokine that acts through a γC-family receptor on target cells and is associated with inflammation and allergy. We determined that T cells from mice deficient in the T helper type 17 (TH17) pathway genes encoding retinoid-related orphan receptor γ (ROR-γ) and IL-23 receptor (IL-23R) produced abundant IL-9, and we found substantial growth inhibition of B16F10 melanoma in these mice. IL-9–blocking antibodies reversed this tumor growth inhibition and enhanced tumor growth in wild-type (WT) mice. Il9r−/− mice showed accelerated tumor growth, and administration of recombinant IL-9 (rIL-9) to tumor-bearing WT and Rag1−/− mice inhibited melanoma as well as lung carcinoma growth. Adoptive transfer of tumor-antigen–specific TH9 cells into both WT and Rag1−/− mice suppressed melanoma growth; this effect was abrogated by treatment with neutralizing antibodies to IL-9. Exogenous rIL-9 inhibited tumor growth in Rag1−/− mice but not in mast-cell–deficient mice, suggesting that the targets of IL-9 in this setting include mast cells but not T or B cells. In addition, we found higher numbers of TH9 cells in normal human skin and blood compared to metastatic lesions of subjects with progressive stage IV melanoma. These results suggest a role for IL-9 in tumor immunity and offer insight into potential therapeutic strategies.

Ref:

http://www.sciencedaily.com/releases/2012/07/120708162314.htm.

http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.2856.html

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