Tuesday, July 20, 2010

Targeted therapy for metastatic melanoma: From bench to bedside..Jim Breitfeller

Targeted therapy for metastatic melanoma: From bench to bedside
Author: Wen-Jen Hwu, MD, PhD

Malignant melanoma is well known for its aggressive clinical behavior, propensity for lethal metastasis and therapeutic resistance. However, in the last decade, considerable excitement has been generated by the identification of genetic mutations in various components of signaling pathways involving melanoma initiation and progression, particularly those involved in the MAP and PI3 pathways. Most recently, clinical trials of pharmacological targeting of relevant molecular targets have demonstrated dramatic response even in patients with late-stage melanoma.

The emerging insights into the mechanisms of activation and negative regulation of innate and adaptive immunity to tumors have provided another breakthrough in melanoma therapy. A new family of immune-based agents of monoclonal antibodies that exert their functions by tampering with immune system cell molecules causing an enhancement of antitumor immune responses has entered clinical trials. In general, these new antitumor agents are designed to break down the barriers to tumor tolerance/immunity. This new group of agents holds promise for at least additive effects with conventional therapies, as well as signal transduction pathway targeted therapies.

Targeting signal transduction pathways

Several key genetic lesions governing melanoma initiation and progression have been identified, the earliest and most common being a point mutation (T1799A) in the BRAF proto-oncogene, which is detected in approximately 60% of metastatic melanoma. BRAFT1799A encodes BRAFV600E, a constitutively active protein serine kinase that elicits sustained activation of the BRAF® MEK1/2® ERK1/2 MAP kinase pathway.

In addition to BRAF, RAS oncogene (rat sarcoma viral oncogene homolog) is another constituent of the MAP kinase pathway. RAS mutations (in one of three isoforms) are found in approximately 20% of metastatic melanoma. RAS is capable of turning on several downstream pathways, including BRAF and other components of MAP kinase pathways, the PI3 kinase pathway, and the RAL-GDS pathway. In general, if a RAS mutation is present, there will be no BRAF mutation. However, the combination of mutated BRAF and silencing of PTEN expression is common in human melanoma (~20%). Dankort and colleagues have demonstrated in a preclinical model that “BRAFV600E cooperates with PTEN loss to induce metastatic melanoma.”

The prevalence of RAS/RAF alterations in human cancer has prompted significant efforts in the development of drugs targeting the MAP kinase pathway. Many of these are currently in clinical trials in patients with metastatic melanoma. Studies with the broad spectrum RAF inhibitor sorafenib (Nexavar, Bayer) as a single agent in patients with BRAF mutated melanoma have proved disappointing. What was unclear from these studies was whether the lack of efficacy was because BRAF was not a critical target or because of incomplete blocking of BRAF by sorafenib.

Since 2005, several BRAF inhibitors have entered clinical trials. These inhibitors are grouped in two categories: BRAF selective inhibitors, and broad spectrum multiple kinases inhibitors with high potency against BRAF.

BRAF inhibitors

PLX4032 (Plexxikon, also known as RO5185426) is a selective BRAF inhibitor and is the first of its kind tested in advanced melanoma. A response rate of 70% in 32 BRAF mutated melanoma patients was reported in the phase 2 study. In general, PLX4032 is well tolerated and most common toxicities include mild-to-moderate skin rash, sun sensitivity, fatigue, arthralgia and keratoacanthoma. Currently, there are two ongoing PLX4032 trials.

Wen-Jen Hwu

The first is a phase 2 study of PLX4032 as a single agent in BRAF mutated melanoma patients who have failed standard therapy for metastatic disease. This study will hopefully confirm the high response rates observed in previous phase 1/2 studies. The second is a phase 3 trial comparing PLX4032 with dacarbazine (standard chemotherapy) in chemotherapy-naive patients with BRAF mutated metastatic melanoma. Seven hundred patients will be enrolled; the primary endpoint is OS.

Another BRAF selective inhibitor is GSK2118436 (GlaxoSmithKline). This drug has already shown promising antitumor activity in the phase 1 portion of a study. The phase 2 portion is ongoing. The impressive high level of antitumor activity of BRAF selective inhibitors indicates that both PLX4032 and GSK2118436 have single-agent activity; BRAF is an important target in melanoma.

Currently, there are at least two nonselective BRAF inhibitors. XL281 (Bristol-Myers Squibb) and RAF265 (Novartis) are in phase 1 testing. Results are expected in the near future.

MEK is a kinase and is immediately downstream of BRAF. It is never mutated in cancer but is activated by BRAF and, in turn, activates the rest of the MAP kinase pathway. In the laboratory, MEK inhibitors have shown activity in a number of BRAF mutated cancers. Currently, there are many MEK inhibitors in clinical trials.

AZD6244 (AstraZeneca) is a MEK inhibitor that has been evaluated most extensively in melanoma. A phase 2 study comparing AZD6244 with temozolomide (oral chemotherapy) has found an objective response rate of 12% among 45 BRAF-mutated patients. However, patients in this study who received temozolomide had a similar response rate and PFS.

Melanomas from acral lentiginous, mucosal and chronic sun-damaged sites frequently harbor activating mutations and/or increased copy number in the KIT tyrosine kinase receptor gene, which are very rare in more common cutaneous melanomas. Multiple case reports and early observations from clinical trials suggested that targeting mutant KIT with small molecule KIT inhibitors such as imatinib (Gleevec, Novartis) and/or dasatinib (Sprycel, BristolMyersSquibb) is efficacious.

Although the dramatic clinical activity of BRAF selective inhibitors is a major breakthrough in the treatment of this disease, there are many hurdles to overcome to optimize this targeted therapy approach. Many of the patients who initially responded to PLX4032 have subsequently progressed with a median duration of response of approximately 8 months. The mechanisms that cause resistance are largely unknown.

Recently, a number of preclinical studies have demonstrated that BRAF inhibitors activate MEK and MAP kinases in melanoma cell lines with wild-type BRAF, including cell lines with mutant NRAS. These studies suggest at least one potential mechanism of resistance is through continued activation of the RAS-RAF-MEK-ERK signaling pathway. Thus, combination agents that target multiple components of this pathway have great potential to overcome drug resistance. Several ongoing clinical trials using the combination of BRAF and MEK targeted agents will be able to test this hypothesis.

Targeting tumor immunity barriers

Since the discovery of monoclonal antibodies in the late 1970s, it has become clear that these antibodies, which are of defined specificity and can be produced in large amounts, had potential for the management of various diseases, including malignancies.

The key property of antibodies to be used as therapeutic tools is their behavior as high-avidity ligands to protein or glycoprotein. Most recently, a new group of monoclonal antibodies that enhance the cellular immune response against cancer have entered clinical trials. These agents bind molecules on the surface of immune system cells. They either provide activating signals to lymphocytes and antigen presenting cells or block the action of receptors that normally down-regulate the immune response.

A humanized monoclonal antibodies (MDX-010, Medarex) against cytotoxic T-lymphocyte antigen 4 (CTLA-4) is the first to reach clinical trials. CTLA-4 is only expressed on the cell surface of activated T cells and regulatory CD4+ CD25+ T cells. In murine models, systemic treatment with transplantable immunogenic colon carcinoma cells with anti-CTLA-4 monoclonal antibodies induced complete tumor regression of established tumors through an immune response found to be critically dependent on the activity of cytotoxic T lymphocytes.

Various phase clinical studies have been conducted on the two anti-CTLA-4 monoclonal antibodies, ipilimumab (Bristol-Myers Squibb) and tremilimumab (Pfizer), as monotherpy, in combination with vaccines or other immunotherapies, and in combination with chemotherapies. Blockade by the T-cell inhibitory molecule CTLA-4 results in antitumor response with overall response rates from 10% to 20%. Most adverse events involve autoimmune toxicities, such as dermatitis, uveitis, colitis/enterocolitis, hepatitis and hypophysitis.

4-1BB (CD137) is a surface glycoprotein that belongs to the TNF receptor family. It is expressed by activated, but not resting, T and NK cells. A humanized anti-4-1BB monoclonal antibody (Bristol-Myers Squibb) has been tested in clinical trials. However, the phase 2 study in refractory melanoma was discontinued in May 2009 due to unusually high incidence of grade-4 hepatitis.

Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals that regulate the balance between T cell activation, tolerance and immunopathology. In vivo studies have shown B7-1 (CD80) is also a binding partner for PD-L1, and their interactions can lead to bidirectional inhibitory response in T cells.

PD-L1 is expressed on many tumors including melanoma and is a component of the immune suppression by the tumor microenvironment. Phase 1/2 experience of the anti-PD-1 monoclonal antibody, MDX-1106 (Medarex, Ono-4538), in refractory or relapsed malignancies was presented at the 2009 ASCO Annual Meeting. Clinical activity against melanoma was observed and, more importantly, no MDX-1106 related severe adverse events were noted.

In 2009, at M.D. Anderson Cancer Center, we participated in a phase 1 study of anti-PD-L1 monoclonal antibody (MDX-1105, Medarex) in refractory metastatic melanoma. MDX-1105 has been tolerated by all patients. Most adverse events were mild and were related to inflammatory responses in the tumors, not immune-related toxicity. Clinical responses were observed at all dose levels (1 mg/kg to 10 mg/kg every 2 weeks). Durable partial responses and stable disease were noted in patients whose disease had progressed after at least one, and as many as five, prior systemic therapies. Based on the low toxicity and impressive clinical activity, a phase 2 study of MDX-1105 in advanced melanoma is warranted.

In summary, the treatment of metastatic melanoma is changing rapidly due to the great success in translational research from bench to bedside. Although such studies, to date, have focused on the treatment of advanced metastatic disease, the approaches of targeting signal transduction pathway, as well as targeting tumor immunity barrier, hold great promise to the development of preventive strategies and personalized therapies in malignant melanoma.

Wen-Jen Hwu, MD, PhD, is a professor in the department of melanoma medical oncology at The University of Texas M.D. Anderson Cancer Center and is a member of the HemOnc Today Editorial Board.


“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,
Jimmy B

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Greetings to One and All

This Blog is dedicated My Brother Kenny B. who passed away in the late 1970's with Cancer before the Internet.

It was he, who showed me How to live and give back. He was wise beyond his years.

Kenny B

Jimmy and Dee

Carepage: Jimmybreitfeller
Jimmy Breitfeller

My Profile as of 2009

My photo
Last July (2005)I was riding my bicycle to work at the Eastman Kodak Research Labs about 3 miles from home. I was wearing a knapsack to carry my things to and from the labs. I started noticing an ache on my back. So I decide to go to the dermatologist. To make the long story short, it was cancer. I knew from my research that I would be needing adjuvant therapy. So I started communicating with Sloan Kettering, University of Pittsburgh Cancer Center, and a couple of others including the Wilmot Cancer Center at Strong. I realized that by telling my story, I might help someone else out there in a similar situation. So to all who are linked by diagnosis or by relation to someone with melanoma, I wish you well. Stay positive, read as much as you can (information helps to eliminate the fear associated with the unknown), and live for today, as no one can predict what tomorrow may bring. Jimmy B. posted 12/15/08


The information contained within this Blog is not meant to replace the examination or advice of your Oncologist or Medical Team. The educational material that is covered here or Linked to, does not cover every detail of each disorder discussed.

Only your physician/Oncologist can make medical decisions and treatment plans that are appropriate for you. But, An Educated Consumer is a Smart consumer.

As Dr. Casey Culberson Said:

"The BEST melanoma patient is an ACTIVE PARTICIPANT in his or her treatment

Melanoma and the “Magic Bullet” (Monoclonal Antibodies)

Just to let you know I posted the first draft of the Melanoma and the “Magic Bullet” (Monoclonal Antibodies). on Melanoma Missionary In the Shared File Section. you can download it for 19.95 (Only kidding) it is Free for the taking.

It is 33 pages long and may help you in your quest for the Yellow Brick Broad. Just to let you know it is only the first draft. Revisions are sure to come. I wanted to get it to the people that need it the most, the Melanoma Patients.


So, where does Interluekin-2 (IL-2) come into play? According to Byung-Scok et al and recent reports, IL-2 is not needed for developmental CD4+ CD25+ Treg cells in the thymus but does play an important role in the maintenance and function in the peripheral.18 Peripheral is defines as secondary system outside the bone marrow and thymus. It entails the site of antigen, immune system interaction. IL-2 is required for the peripheral generation of Tregs based Abbas’s and colleagues research.19

IL-2 prevents the spontaneous apoptosis of the CD4+ CD25+ Treg cells. It has been reported that patients with multiple advance-stage tumors have elevated levels of Tregs within the tumor microenviroment.20 Interluekin-2 is the survival factor for CD4+ CD25+ Treg cells.21 If the addition of IL-2 is on or before the maximum propagation of the CD4+ T cells, the Tregs population can increase 5-fold in a 96 hour period based on certain growth mediums.

By controlling the addition of the endogenous IL-2, one has a knob to turn and can lead to the control of the expansion of the Tregs. When you combined this control with the anti-CTLA-4 blockage, you can shift the balance of the immune response.

Now here is the catch. The maintenance and function of the CD8+ T-cells require CD4+ cells which secrete IL-2. So we don’t want to deplete the CD4+ cells, we want to control the expansion of the Tregs which are a subset of the CD4+ cells. It has been postulated by some researchers that the Anti-CTLA-4 blockage also suppresses the Treg function in a different mechanism. By using IL-2 as the rate limiting factor, we can suppress the CD4+ CD25+ Treg cell expansion by controlling the concentration and timing of the Inerluekin-2 at the tumor microenvironment.

The Interluekin-2 plays another role in this Melanoma Maze. In a study by Janas et al, Il-2 increases the expressions of the perforin and granzyme A, B and C genes in the CD8+ T-cells. This increase expression causes the CD8+ T-cells to mature into Cytoxic T Lymphocytes (CTLs). The exogenous IL-2 is required for the granzyme proteins. As stated previously, CTLs have cytoplasmic granules that contain the proteins perforin and granzymes. A dozen or more perforin molecules insert themselves into the plasma membrane of target cells forming a pore that enables granzymes to enter the cell. Once in the tumor cell, these enzymes are able to breakup (lyse) the cell and destroy it. This is the beginning of the end for the cancer cells. The tumors begin to shrink and the rest is history,

On the other hand, prolong therapy with Il-2 can result in causing apoptotic death of the tumor- specific CD8+ T-cells.23

Clearly in a clinical setting, timing, dose, and exposure to these drugs play a major roll in the immunotherapy, and can have dramatic effects on the outcome.

All it takes is that one magic bullet to start the immune reaction..


Melanoma And The Magic Bullet (Monoclonal Antibodies)

Public Service Announcement

A call for Melanoma Patients by Dr. Steven A Rosenberg

"We continue to see a high rate of clinical responses in our cell transfer immunotherapy treatments for patients with metastatic melanoma", Dr. Rosenberg said.

"We are actively seeking patients for these trials and any note of that on a patient-directed web site would be appreciated."

If you would like to apply for his trials, here is the website and information.

Dr. Rosenberg's information

Dr. Rosenberg's Clinical Trials

For the Warriors

The Melanoma Research Alliance has partnered with Bruce Springsteen, the E Street Band, and the Federici family to alleviate suffering and death from melanoma. Please view Bruce Springsteen’s public service announcement inspired by Danny Federici. Danny was the E Street Band’s organist and keyboard player. He died on April 17, 2008 at Memorial Sloan-Kettering Cancer Center in New York City after a three year battle with melanoma.


Source Fastcures blog

Join the Relay for Life!!!


Dear Family and Friends,

I’ve decided to take a stand and fight back against cancer by participating in the American Cancer Society Relay For Life® event right here in my community! Please support me in this important cause by making a secure, tax-deductible donation online using the link below.

To donate on line now, click here to visit my personal page.
Jimmy B AKA Melanoma_Missionary

Relay For Life® is a life-changing event that brings together more than 3.5 million people worldwide to:

CELEBRATE the lives of those who have battled cancer. The strength of survivors inspires others to continue to fight.

REMEMBER loved ones lost to the disease. At Relay, people who have walked alongside people battling cancer can grieve and find healing.

FIGHT BACK. We Relay because we have been touched by cancer and desperately want to put an end to the disease.

Whatever you can give will help - it all adds up! I greatly appreciate your support and will keep you posted on my progress.

Keep the Fire Burning!!!



Jimmy Breitfeller
Turn off Music before you "Click to Play"
Signs of Melanoma Carcinoma Skin Cancer

How Skin Cancer Develops by "About.com : Dermatology"

Call for Patients with Unresectable Liver Metastases Due to Melanoma

Delcath Systems Granted Orphan-Drug Designations for Cutaneous and Ocular Melanoma

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.

Current Trial Centers

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

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)

Blog Archive

Call For Melanoma Patients!!!!

Call For Melanoma Patients!!!!

Dr. Rosenberg Has a New Clinical Trial.

Our latest treatment has a 72% objective response rate with 36% complete responses.

We are currently recruiting patients for our latest trial.

Is there some way to post this “Call for Patients” on the web site?

Steve Rosenberg

Dr. Rosenberg's Clinical Trials

(For a copy of the research paper.. see My Shared files)

The news headlines shown above for Melanoma / Skin Cancer are provided courtesy of Medical News Today.