Driving in the Melanoma Landscape.. Jim Breitfeller

Driving in the melanoma landscape
Viewpoint
Dr. Meenhard Herlyn
The Wistar Institute, Philadelphia, PA, USA

Abstract: The melanoma landscape is rapidly evolving. The
melanoma oncologists have now the first successful targets for
therapy that have a genetic base – albeit in rare forms of the
malignancy. Once melanoma becomes part of the Cancer Genome
Atlas consortium, a comprehensive map of genetic changes will be
established to point the field to true drivers of the disease that
will become new targets for therapy. The same abnormalities will
also serve as biomarkers for diagnosis, prognosis and therapy
follow-up. Melanomas as a group are heterogenous as are tumor
cells within one lesion. New strategies will move towards
individualized therapies and combination therapies to target all
cells within a tumor.

Driving in the melanoma landscape


Please take time to read this viewpoint from a world renowned Researcher in Cancer





http://www.box.net/shared/kjgr6dkztj


Melanoma and The Magic Bullet (Monoclonal Antibodies)




Take Care,

Jimmy B

ew Method Takes Aim at Aggressive Cancer Cells..Melanoma ..Jim Breitfeller

Released: Mon 10-Aug-2009, 11:00 ET

Newswise — A multi-institutional team of Boston-area researchers has discovered a chemical that works in mice to kill the rare but aggressive cells within breast cancers that have the ability to seed new tumors.

These cells, known as cancer stem cells, are thought to enable cancers to spread — and to reemerge after seemingly successful treatment. Although further work is needed to determine whether this specific chemical holds therapeutic promise for humans, the study shows that it is possible to find chemicals that selectively kill cancer stem cells. The scientists’ findings appear in the August 13 advance online issue of Cell.

“Evidence is accumulating rapidly that cancer stem cells are responsible for the aggressive powers of many tumors,” says Robert Weinberg, a Member of Whitehead Institute for Biomedical Research and one of the authors of the study. “The ability to generate such cells in the laboratory, together with the powerful techniques available at the Broad Institute, made it possible to identify this chemical. There surely will be dozens of others with similar properties found over the next several years.”

“Many therapies kill the bulk of a tumor only to see it regrow,” says Eric Lander, Director of the Broad Institute of MIT and Harvard, and an author of the Cell paper. “This raises the prospect of new kinds of anti-cancer therapies.”

An emerging idea in cancer biology is that tumors (breast, prostate, colon, lung, etc.) harbor a group of cells with the unique ability to regenerate cancers. In addition to promoting tumor growth, these so-called cancer stem cells are largely resistant to current cancer therapies. If it were possible to identify chemicals that selectively kill cancer stem cells, such chemicals might become critical candidates for future drug development.

However, researchers have struggled to study cancer stem cells directly in the laboratory. The cells’ relative scarcity compared to other tumor cells, combined with a tendency to lose their stem cell-like properties when grown outside of the body, have severely limited the amount of material available for analysis.

To overcome these hurdles, Broad and Whitehead Institute researchers drew upon recent findings from Weinberg and his colleagues that suggested a way to generate in the laboratory large numbers of cancer cells with stem cell-like qualities. The technique works by coaxing adult cells to undergo a critical change (known as an “epithelial-to-mesenchymal transition”) that alters their shape and motility. At the same time, the cells also adopt similar properties as stem cells.

“A critical aspect of our work was to generate relatively homogenous and stable populations of cancer stem-like cells that could then be used for screening,” says Tamer Onder, a former graduate student in Weinberg’s lab and co-first author of the study. (Onder is now a postdoctoral research fellow at Children’s Hospital in Boston.) “We were able to achieve this by inducing the cancer cells into an epithelial-to-mesenchymal transition using novel reagents that we had developed in the lab.”

With an ample number of stem cells in hand, the Broad-Whitehead team undertook a large-scale analysis of thousands of chemical compounds, applying automated methods to search for ones with activity against breast cancer stem cells. From a pool of more than 30 promising candidates, the researchers identified a compound with surprising potency.

The compound, called salinomycin, kills not only laboratory-created cancer stem cells, but also naturally occurring ones. Compared to a common chemotherapeutic drug prescribed for breast cancer (known as paclitaxel), salinomycin reduced the number of cancer stem cells by more than 100-fold. It also diminished breast tumor growth in mice.

To further dissect the function of salinomycin, the researchers also examined its genetic effects. Previous studies of tumors from breast cancer patients have revealed groups of genes that are highly active in cancer stem cells. Many of these same genes are linked with particularly aggressive tumors and poor patient prognoses. The researchers’ studies show that salinomycin (but not paclitaxel) treatment can decrease the activity of these genes, revealing a possible molecular basis for the chemical’s biological effects.

“Our work reveals the biological effects of targeting cancer stem cells,” says co-first author Piyush Gupta, a researcher at the Broad Institute. “Moreover, it suggests a general approach to finding novel anti-cancer therapies that can be applied to any solid tumor maintained by cancer stem cells.”

Although the new findings signal a noteworthy scientific milestone, it is still too early to know whether cancer patients will reap benefits from it. Additional research is needed to determine exactly how salinomycin works to kill cancer stem cells and if it can wield the same tumor-reducing power in humans as it does in mice. These types of analyses generally take several years to complete.

But even with such tempered enthusiasm, there is also cause for optimism. In the current study, just 16,000 chemical compounds were tested, of which a small subset showed toxicity against cancer stem cells. Therefore, deeper investigations of these compounds as well additional tests of broader collections of chemicals may yield other potential additions to the anti-cancer arsenal.

Paper cited:
Gupta et al. “Identification of selective inhibitors of cancer stem cells by high-throughput screening.” Cell, published online August 13, 2009

A complete list of the study’s authors and their affiliations:

Piyush B. Gupta,1,3,7,* Tamer T. Onder,1,2,7 Guozhi Jiang,1,3 Kai Tao,4 Charlotte Kuperwasser,4 Robert A. Weinberg,1,2,6,8,* and Eric S. Lander 1,2,3,5,8,*

1Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

2Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA

3Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA

4Department of Anatomy and Cell Biology, Tufts University School of Medicine and Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA

5Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA

6MIT Ludwig Center for Molecular Oncology, Cambridge, MA 02139

7These authors contributed equally to this work

8These authors contributed equally to this work

*Corresponding authors

About the Whitehead Institute for Biomedical Research
Whitehead Institute for Biomedical Research is a nonprofit, independent research and educational institution. Wholly independent in its governance, finances and research programs, Whitehead shares a close affiliation with Massachusetts Institute of Technology through its faculty, who hold joint MIT appointments. For additional information about Whitehead Institute, please visit www.whitehead.mit.edu.

About the Broad Institute of MIT and Harvard
The Eli and Edythe L. Broad Institute of MIT and Harvard was founded in 2003 to empower this generation of creative scientists to transform medicine with new genome-based knowledge. The Broad Institute seeks to define all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.

Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to www.broad.mit.edu

Information hot off the press


Take Care,

Jimmy B

ASCO summary By Dr. Eric Whitman.. Melanoma ..Jim breitfeller

ASCO Summary
Posted on June 1, 2009 by dr Eric Whitman

"I have been going to ASCO for years and I’m still waiting for that “a-hah!” moment when somebody presents something for melanoma that is so revolutionary and effective that we all have something tangible and exciting to come home with and build on in the future. I feel like we are getting closer as a “melanoma community.” I know that in my own clinical experience and current practice, I am able much more frequently to walk into someone’s exam room and tell them, congratulations, the tumors are shrinking. Honestly, there were many years where that **never** happened.

However, for all the hopes extended each year towards ASCO as the ultimate cancer meeting, I honestly can say that there was nothing presented over the last few days that will immediately change therapy or even holds out hope for some drug or combination of drugs posterizing DTIC or Temodar. (Posterizing somebody is a reference to pro basketball, when you savagely dunk the basketball over an opponent with such force and superiority that it becomes an instant classic athletic poster. Like the Michael Jordan slam dunk contest when he still had hair, took off from the foul-line, and the open mouth, wide-eyed stares of the sideline onlookers were forever captured.)

The closest we came in my career was the early data from about 2004 on Sorafenib/Nexavar, but that has melted away with larger scale, multicenter studies and is just a footnote at this point.

I will provide more detailed updates in other posts, but unfortunately there are no new treatments that show undeniable improvement over existing treatments. There are a few things that suggest the potential for improved therapy, but these are best described as “hypothesis-generating” or in other words, deserving of further, large scale, testing.

I know that this is frustrating to the melanoma patient community also; we’re just not there yet. We have new drugs coming down the road and they do have promising early results but the emphasis has to be on the word, promising.

The two take home words this year from the ASCO melanoma presentations were “Biomarkers” and “Targeted therapy”. In that regard, I don’t think the melanoma talks were that different from other disease areas. Biomarkers are things that can be measured, either in the blood or tumor tissue (or even in normal tissue) that classify an individual’s cancer by its behavior or potential to resp0nd to specific therapies. A biomarker could also monitor a patient’s response to therapy. A good example of this is the PSA level for prostate cancer. Finally, biomarkers could also identify patients either at risk for bad outcomes or those likely to respond to specifc treatments.

Targeted therapy refers to drugs that alter cellular biochemical pathways that are believed to influence a cancer cell’s ability to survive, grow, and/or resist therapy. Presumably, targeted therapy would have fewer side effects that standard chemotherapy but this exaggerates our true knowledge about these various pathways and their role in normal, non-cancerous, tissue. The other caveat about targeted therapy is that many of the ones that look most promising (to me) act by increasing cancer cells’ responsiveness to standard chemotherapy. As a result, these targeted agents often have no effect by themselves (ie monotherapy) and require simultaneous (concurrent is the medical word) chemotherapy drugs which obviously cause a range of side effects.

As you read my other summaries of ASCO papers and posters, keep biomarker and targeted therapy in the back of your mind; they came up over and over again"


WE NEED TO FIND THE “a-hah!” MOMENT!!!

I personally think we are getting closer.

The first step is to initiate the immune response

As our fellow carepage friend Jen has said, " DON'T STOP BELIEVING!!!!"

Take care

Jimmy B

Targeted Therapy ...Ocular/unveal Melanoma ..Jim Breitfeller

As I continue my series on Targeted Therapy, I was contacted and was asked to put the word out for Ocular Melanoma Patients. Well I did not know very much about this cancer. So, I decided to research it before I said anything.

About 2000 people get diagnosed with Ocular Melanoma a year. Ocular melanoma is a lethal and very rare disease. Many people die from it, especially when it spreads to the liver, a common complication. There are other types of eye cancers, but melanoma is the most common.

Ocular melanoma, a rare cancer, is a disease in which cancer (malignant) cells are found in the part of the eye called the uvea. The uvea contains cells called melanocytes. When these cells become cancerous, the cancer is called a melanoma. The uvea includes the iris (the colored part of the eye), the ciliary body (a muscle in the eye), and the choroid (a layer of tissue in the back of the eye). The iris opens and closes to change the amount of light entering the eye. The ciliary body changes the shape of the lens inside the eye so it can focus. The choroid layer is next to the retina, the part of the eye that makes a picture. If there is melanoma that starts in the iris, it may look like a dark spot on the iris. If melanoma is in the ciliary body or the choroid, a person may have blurry vision or may have no symptoms, and the cancer may grow before it is noticed. Intraocular melanoma is usually found during a routine eye examination, when a doctor looks inside the eye with special lights and instruments.1

The chance of recovery (prognosis) depends on the size and cell type of the cancer, where the cancer is in the eye, and whether the cancer has spread.

What are the Symptoms?
“Ocular melanoma may not cause any early symptoms. It is sometimes found during a routine eye exam when the doctor dilates the pupil and looks into the eye. The following symptoms may be caused by intraocular melanoma or by other conditions. A doctor should be consulted if any of these problems occur:”2


• A dark spot on the iris.
• Blurred vision.
• A change in the shape of the pupil.
• A change in vision.

If it is caught early, it is curable. Left untreated this melanoma usually metastasizes to the liver and onto other sites. It is very difficult to treat once it has metastasize. Uveal melanoma can be effectively treated, but once it metastasizes to
the liver, survival can be less than 6 months.



What are the Known Treatments?
A good web site to go for information from Patients like us is:
http://www.lafn.org/~bc534/OcularMelMets.htm

Uveal Melanoma Metastatic to the Liver


There are at least five different treatments for Ocular (uveal) melanoma patients who have liver metastases.

Immunoembolization

“Immunoembolization is a variation of chemoembolization, which involves infusing a
cytotoxic agent into a tumor after mechanically or surgically disrupting the tumor's
blood supply. The advantage of immunoembolization is that it
could attract and stimulate antigen-presenting cells in liver tumors and improve the
uptake of tumor antigens released from necrotic tumor cells, as well as potentially
facilitate a systemic immune response against tumor cells and thereby suppress the
growth of extrahepatic metastases.”3


Stereotactic Body Radiosurgery

“Stereotactic body radiosurgery(SBR) is a novel treatment that can be employed in the treatment of metastatic melanoma. Stereotactic body radiosurgery is a treatment that uses multiple high powered beams aimed very precisely at tumors in the body. The Elekta frame immobilizes the patient and decreases the movement of the liver and lung tumors due to breathing. The treatment spares normal tissue because of its extreme precision. The treatment is completely non invasive and is given in 1-3 outpatient treatments. Patients can continue there normal daily activites as there are often minimal side effects. Metastic melanoma, melanoma that has spread to other organs, is a difficult situation because there is not effective drug therapy. Occasionally, if possible, the tumors can be surgically removed. However, surgery is usually not possible and can be quite morbid with extensive recovery times. Much as surgery, Stereotactic body radiosurgery can eradicate treated tumors in the lung and liver 90 percent of the time. Unlike surgery, there is very little risk and minimal side effects. Patients are able to continue their daily activities without difficulty. The high tumor eradication rate is a result of its high dose per treatment.

Patient with recurrent metastatic melanoma or diagnosed initially with metastatic melanoma are potential candidates. Patients need to have relatively few liver or lung metastasis and have good funtional status. Some doctors have arbitrarily set the limit to 5 tumors.”4




Radiofrequency Ablation

“Radiofrequency ablation (RFA) is an exciting technique used to treat malignant liver tumors. An electrical current is transmitted through a small needle placed directly into a liver tumor, to destroy cancer cells with heat. An array of hook electrodes are deployed from the tip of the needle after it's placed in the tumor. The hook electrodes look like the ribs of an umbrella, with a diameter of 3.5 centimeters (slightly greater than an inch) when fully deployed (figure 1). An ultrasound probe is used to guide placement of the needle, and after the needle is in the correct area, the hook electrodes are deployed into the liver tumor. The treatment is started by applying electrical current from a small, briefcase-sized device called a radiofrequency current generator. The amount of power supplied by the generator can be controlled precisely, and the generator is also used to monitor the treatment until complete heat-induced destruction of the tumor being treated occur.”
“The key in each of these patients is that the liver was the only cancer site. We do not perform RFA in patients with cancer that has spread to other areas or organs, because treating only the liver will not improve these patients’ chances for survival. We also have learned that it is difficult, and probably not helpful, to treat patients with more than eight tumors, or if more than half of their liver is replaced by tumors. Lastly, we find that the RFA equipment currently available does not reliably destroy all the tumor if it is larger than six centimeters in diameter. These larger tumors should be removed when possible. Thus, we do not recommend RFA for these larger liver tumors, but we, and others, are working to develop RFA systems that will effectively treat larger tumors. 5”


Chemoembolization.

A procedure in which the blood supply to the tumor is blocked surgically or mechanically and anticancer drugs are administered directly into the tumor. This permits a higher concentration of drug to be in contact with the tumor for a longer period of time. Unlike conventional systemic chemotherapy, the drugs injected through the hepatic artery are confined to the liver. Side effects of chemotherapy are minimized as a result.




Isolated Liver Perfusion

This treatment for liver tumors was first described over thirty years ago but has had limited clinical use until now. The basis of this treatment is to expose the liver to high doses of chemotherapy in order to achieve maximal tumor shrinkage. The blood supply to the liver is completely isolated from the systemic circulation so that the body is not exposed to the high dose of drugs. It requires a lengthy operation to completely mobilize the liver and to insert catheters into the hepatic artery, portal vein and hepatic veins.
Recently, initial results using different drugs have been encouraging and work continues with this modality. This is experimental therapy and should only be used in a clinical trial.





Patients with isolated hepatic metastasis from Ocular Melanoma are indeed rare. In the largest prospective data base on melanoma in the world (the combined experience of The John Wayne Cancer Institute and Sydney Melanoma Unit) only 24 of 1750 patients (1.3%) with hepatic metastasis were found to have disease that was resectable6

Since the most of the patients would have non-resectable with hepatic metastasis, I have been contacted by Delcath Systems that is the sponsor of the trial.

“I oversee Delcath Systems' National Cancer Institute-led Phase III clinical trial for metastatic melanoma to the liver. As you know, there are few effective treatment options for patients once melanoma has metastasized to the liver, however, we are highly encouraged by our current clinical trial, which showed tremendous response rates in its corresponding Phase I study. We are treating patients at a number of cancer centers throughout the country using a minimally invasive procedure that targets the liver for high dose drug treatment. In addition to overseeing the operations of this trial, I am also trying to increase the awareness of its availability to patients, medical oncologists, surgical oncologists, dermatologists and other physicians.”


Phase I Study of Hepatic Arterial Melphalan Infusion and Hepatic Venous Hemofiltration Using
Percutaneously Placed Catheters in Patients With Unresectable Hepatic Malignancies



Delcath Systems Granted Orphan-Drug Designations for Cutaneous and Ocular Melanoma
NEW YORK, November 18, 2008 – Delcath Systems, Inc. (Nasdaq: DCTH), a medical technology company testing its proprietary liver cancer treatment for melanoma metastatic to the liver, announced today that the United States Food and Drug Administration (“FDA”) granted to Delcath two orphan-drug applications for the drug melphalan. Delcath was granted designations of the drug melphalan for the treatment of patients with cutaneous as well as ocular melanoma. Approximately 65,000 cases of these melanomas are diagnosed annually in the United States.
Delcath is actively enrolling patients in a Phase III clinical trial testing its proprietary drug delivery system, known as Percutaneous Hepatic Perfusion (“PHP”), with melphalan for the treatment of ocular and cutaneous melanoma metastatic to the liver. This NCI-led trial is enrolling patients at leading cancer centers throughout the United States. Commenting on these orphan-drug designations, Richard L. Taney, President and CEO of Delcath, stated, “These favorable designations are important steps in our efforts to secure Delcath’s commercial position upon conclusion of our pivotal Phase III trial for metastatic melanoma. We remain steadfast in our commitment to become the leader in the regional treatment of liver cancers and we continue to enroll patients in this study, and advance our technology and the promise that it offers to patients with these deadly forms of melanoma and other cancers of the liver, all with limited treatment options.”
Orphan drug designation, when granted by the FDA’s Office of Orphan Products Development, allows for up to seven years of market exclusivity upon FDA approval, as well as clinical study incentives, study design assistance, waivers of certain FDA user fees, and potential tax credits.
Source: Delcath Systems Inc.


So, I went out and tried to contact the Oncologists that are participating in the trial.


http://www.delcath.com/news/2008/treatmentcenters.html

Current Trial Centers



Oncologist’s Comments:

“We are participating in the percutaneous hepatic perfusion with melphalan trial. This treatment is for patients with melanoma metastatic to the liver (either from the eye or skin), with little or no melanoma elsewhere. The response rates so far are high (the majority of patients respond in the liver) and patients have tolerated the perfusion well. The main risks have to do with the thinning of the blood that occurs during the perfusion and the possibility of the chemotherapy escaping the isolated area and affecting other parts of the body, but problems have been rare. The main disadvantage is that the rest of the body is not treated, only the liver. This is fine if the areas of melanoma are restricted to the liver exclusively, or almost exclusively. Obviously there is a lot more to it, but I’d be happy to give more information if anyone had specific questions.”


“One good thing about the perfusion trial is that, though it is randomized, there is the potential for “crossover”. That is, patients are assigned to get the perfusion or get the best alternative care (almost any alternative is allowed), and if their liver disease grows on the other therapy, they can switch over to the perfusion. If it were me, I would do the perfusion trial if I had unresectable, liver only metastases.

The leakage is rare and has not happened at all to my knowledge since some protocol changes were implemented.

Every patient is different and I would encourage everyone to explore options and go to a melanoma center where the most options can be considered.”

“Because this is an active ongoing Phase III clinical trial there is no preliminary data to give. What I can tell you is that the technique and the phase I data was published in a the Journal of Clinical Oncology in May 2005. Because we did have some great responses in melanoma patients, we are testing this technique against the best available therapy. This technique is best used for patients with disease confined to the liver but there are exceptions to this.”


As usual, I was in contact with Dr. James Pingpank, author and principle investigator of:

Phase I Study of Hepatic Arterial Melphalan Infusion and Hepatic Venous Hemofiltration Using Percutaneously Placed Catheters in Patients With Unresectable Hepatic Malignancie.


He was encouraged with the results so far.


James F. Pingpank, Jr., MD, FACS
Associate Professor of Surgery
Division of Surgical Oncology
Suite 406, UPMC Cancer Pavillion
5150 Centre Avenue
Pittsburgh, PA 15232
412-692-2852 (Office)
412-692-2520 (Fax)
PingpankJF@UPMC.edu


My Take on the subject as I see it:

This very hard disease to treat.

This Therapy is not a cure all, but it seems to extend the survival for most patients while maintaining a good quality of life base on the disease.

As one Oncologist said “Every patient is different and I would encourage everyone to explore options and go to a melanoma center where the most options can be considered.”


References

1. http://www.kellogg.umich.edu/patientcare/conditions/intraocular.melanoma.html
2. http://www.cancer.gov/cancertopics/pdq/treatment/intraocularmelanoma/Patient#Keypoint3
3. Immunoembolization safe, promising for liver metastases from uveal melanoma October 24, 2008 American Society of Clinical Oncology
4. http://www.cancertreatmentgroup.com/metastatic_melanoma.shtml
5. http://www.mdanderson.org/departments/ltsg/display.cfm?id=6193B8E8-BC8D-11D4-80FB00508B603A14&pn=9DF6DAEE-7AAF-430F-8ADC4CAF62712136&method=displayfull

6. Rose DM, Essner R, Hughes TM, et al. Surgical resection for metastatic melanoma to the liver: the John Wayne Cancer Institute and Sydney Melanoma Unit experience. Arch Surg 2001; 136: 950–5.



Take care

Jimmy B
Melanoma_Missionary