Lexicillin QD

NY York Cancer Consortium Annual Developmental Therapeutics Symposium

This is the agenda for this Friday's New York Cancer Consortium Annual Developmental Therapeutics Symposium:

8:10-8:15 AM  Introductory Remarks

Joseph A. Sparano, MD

The Epigenome as a Therapeutic Target     

Session Chair: Ari Melnick, MD

8:15-8:45 AM   Epigenomics in Disease Pathogenesis

John Greally, MD

8:45 AM - 9:15 AM  Therapeutic Targeting of the Epigenome

Ari Melnick, MD

9:15 AM - 9:45 AM  Clinical Application of Epigenomic Therapy 

Guido Marcucci, MD

9:45 AM- 10:00 AM  Panel Discussion

10:00-10:15 AM  Coffee break

New Therapeutic Targets     

Session Chair: Franco Muggia, MD

 

10:15-10:45 AM   c-Met Inhibitors

Joseph P. Eder, MD

10: 45-11:15 AM   HSP and Aurora Kinase Inhibitors

Kapil Bhalla, MD

11:15 AM – 11:45 AM  Hot Stuff in the CTEP Pipeline

Jamie Zwiebel, MD

11:45 AM-12:00 PM Panel Discussion 

12:00 PM – 1:00 PM   Lunch and Overview of NYCC Portfolio

Clinical Trial Designs     

Session Chair: Joseph A. Sparano, MD

1:00–1:45 PM   Scott Walder Memorial Lecture

   The Phase II Trial: Resource or Relic?

James Doroshow, MD

1:45 - 2:30 PM   Adaptive Trials Designs: Past, Present, and Future

Donald A. Berry, PhD

2:30-2:45 PM    Panel Discussion

2:45-3:00 PM    Coffee break

Highlights of 2008 AACR Meeting     

Session Chair: John Leonard, MD

3:00-3:45 PM    Translational and Novel Therapeutics - Solid Tumors

Eric Rubin, MD

3:45-4:30 PM    Translational and Novel Therapeutics -Hematologic Malignancies

Janice Gabrilove, MD

4:30 – 4:45   Panel Discussion

Meeting Adjournment

Ipilimumab: Bristol-Myers, Medarex cancer drug delayed

Ipilimumab, the fully human antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), is in clinical trials for the treatment of advanced melanoma, but Reuters is reporting:

Bristol-Myers Squibb Co and Medarex Inc  said Friday they will delay seeking approval of their experimental treatment for advanced melanoma after U.S. health regulators requested additional data on the biotechnology drug.

Because of this, an approval application will not be submitted this year.

The epigenome as a therapeutic target

Epigenetics is certainly a hot topic when it comes to discussing the future of cancer therapy using biologics. For those interested, a review article was published in the NEJM last month.

It's one of the topics to be discussed at the upcoming New York Cancer Consortium (NYCC) Third Annual Developmental Therapeutics Symposium to be held May 16th here in NYC.

Basically, epigenetics is the study of variations in gene expression not due to changes in the base sequence of DNA, even though it's effect can be inherited. The most striking example is when you look at identical (monozygotic) twins. Early on in life, the genes expressed by each twin are similar. If they are raised in different environments or have different lifestyle choices e.g., diet and smoking, this expression pattern can change so that eventually one twin might be more susceptible to cancer than the other. So far the markers for this change in expression are DNA methylation and histone modification. (The histones are the protein spools around which DNA is wrapped.) Hypomethylation of DNA in colon cancer has been known since 1983.

 

Last Friday, I attended NYCC's annual review of symposia by the various cancer societies. The presenters reviewed papers studying the DNA hypomethylating agents azacytidine and decitabine which already have FDA-approval for treatment of myelodysplastic syndrome. The histone deacetylase (HDAC) inhibitor vorinostat is being tested for other uses besides cutaneous T-cell lymphoma.

Monday I was at the New York Blood Center where they hosted a conference on umbilical cord blood banking. "Ex Vivo Expansion of Cord Blood Products" was the title of the talk by Ronald Hoffman, MD who is a professor at the Mount Sinai School of Medicine and Director of Myeloproliferative Disorders Research Consortium. He talked about his efforts in trying to expand the volume of the typical umbilical cord blood unit by prompting these cells to replicate without differentiating into mature cells. Currently, it requires two units to transplant an adult who is being treated for leukemia or other blood disease. This additional unit complicates things since there has to be some matching done against the recipient's immune system.

Hoffman found that he could expand the number of stem cells, as identified by various surface markers, but they didn't work was well in engrafting in the recipient as the the primary cord blood unit. His hypothesis was that somehow the critical genes were being silenced by epigenetic factors. To counteract this, he used chromatin modifiers: a DNA hypomethylating agent and histone deacetylase inhibitor to reverse the possible silencing. He found better results in engraftment with this experimental treatment.

Once I get a chance to read more on his published results or inteview him directly, I'll be able to talk more in detail in a later post.

New York Blood Center: treating hematologic diseases with umbilical cord transplant

I'm just starting to catch up with blogging about the various conferences I've been attending.

Last Friday I attended the annual New York Cancer Consortium review of the recent American Society of Hematology, and San Antonio Breast Cancer, and America Society of Clinical Oncology symposia. (I'll get to that in a future post.)

Yesterday, I was at the New York Blood Center's one-day conference on the current research being performed with umbilical cord blood, which is supplied via their public cord blood bank, the oldest and largest in the US.

The reality is this: last year, there were 4 million births, and in 99% of the cases, the cord blood was discarded as medical waste.

The parents to be do have the option of banking the infant's cord blood with a private bank. This could cost up to $2,000 for the collection procedure, and up to $200 per year for storing the sample. The American Academy of Pediatrics doesn't recommend this unless there is a family member who has a hematological disease and therefore might benefit if the match is close.

The New York Blood Center provides a public blood banking service where the sample is collected, analyzed for immunological markers, and then stored. These units are either used for research or used for transplantation depending if a close match can be made with the recipient.

The limiting factor now is the sample size. The success of a transplant is dependent on the recipient's weight. Right now the average cord blood unit is about 50 mL, or enough to transplant a 50 kg (110 lb patient). If the average adult with leukemia is to be treated, they need to be transplanted with two units of umbilical cord blood cells, which makes matching even that more difficult, and presents other problems.

The push is on to develop a technique where a lab could take a small umbilical cord blood sample and expand it ex vivo. This means finding the right culture techniques to allow the stem cells to reproduce without producing mature cells so that you can produce enough volume to transfuse an adult with a blood disease. The first researchers who can come up with a reliable technique will change the landscape of how these diseases are treated.

As of now, the 8/8 HLA-matched bone marrow transplants remain the gold standard, but with umbilical cord stem cells, there is less stringency with HLA matching, plus it can be done faster. Currently, it takes several months to prepare a bone marrow donor specimen. With cord blood it's just a matter of thawing the sample and then infusing into a patient through a catheter in the chest.

There is also the possibility that cord blood has some anti-leukemic properties, that is NK (natural killer) cells have been shown to attack leukemic cells. There is also lower graft-versus-host disease with cord blood stem cells.

New York Cancer Consortium's annual review of oncology symposia

This Friday, the New York Cancer Consortium will hold their annual CME event: Review of Meeting Highlights from the ASH 2007, SABCS 2007, and ASCO GU & GI Symposia.

This will be my second year attending this event. I've also been going to their Developmental Therapeutics Symposium every year. This year it will be held on May 16th.

Prostate Cancer update

My personal experience with this disease included processing the core biopsies as a pathology resident at the NYU Medical Center, and then sitting down at the group microscope while the attending pathologist would go through the slides. His report with the Gleason score determined the surgeon's action.

I'll put together some posts based on my experiences to give my readers an idea of what the techniques such as the transrectal ultrasound-guided prostate biopsy and the aspects of diagnosis such as the Gleason scale involve.

But for now, these are some items provide to me by the Prostate Cancer Foundation:

Asian Men More Likely to Survive Prostate Cancer
The reasons behind the better survival rates still unclear

Study Adds to Debate Over Prostate Cancer Testing
More frequent screening did not cut number of cases of aggressive tumors

Red Wine Chemical Guards Mice From Prostate Tumors
Resveratrol-fed mice were nearly eight times less likely than the control mice to develop poorly differentiated prostatic tumors

Low-Fat, Vegetarian Diet May Stall Prostate Cancer
Fiber and other nutrients found in plant-based diets may affect prostate cancer by altering levels of certain hormones that can feed tumor development

Veggies May Lower Aggressive Prostate Cancer Risk
Broccoli and cauliflower appeared to have the biggest impact

Lumpectomy Possible for Some Prostate Tumors
Focal ablative therapy may be an effective and less invasive approach for a considerable minority of men with early prostate cancer that is confined to the prostate

Tangerine peel compound investigated as possible cancer therapy

Salvestrol Q40 is the compound derived from the tangerine peel, and it has been shown to inhibit the enzyme P450 CYP1B1, found in human cancer cells.

This topic is being presented at the British Pharmaceutical Conference.

The P450 enzymes are part of cytochrome systems, usually involved with electron transfer and metabolism. The "P450" refers to the heme pigment which cause at 450 nm with absorption spectroscopy.

Tangerine peel could help fight cancer | Health | Reuters

Technorati Tags: salvestrol, cancer, p450, tangerine

Extremophiles thriving in toxic waste, subject of cancer research

This is the unlikely and highly ironic story about 37 billion gallons of toxic waste water sitting in a lake generated from an abandoned strip mine, acting as the home for very hearty bacteria known as extremophiles, which are being studied by cancer researchers for a possible future therapy.

This is a piece published in the latest issue of Wired, written by Guy Gugliotta who I recently telephoned to get more info about this story.

The Berkeley Pit Lake in Butte, Montana was designated one of the first Superfund sites by the government some 25 years ago. Since then all that can be done is to try to maintain the water level at a constant height.

Cancer researchers became interested in the resident extremophiles since they might produce unique compounds that might have therapeutic activity.

As it turned out, several cancer cell lines were shown to be inhibited by these compounds, but this is only the beginning stages of working them up as possible anticancer candidates.

 

Another potential therapy for fighting cancer using p53

This follows from my post on Dr Pincus' research using a p53-derived protein to attack cancer cells.

This animation on YouTube, which was produced at the Howard Hughes Medical Institute and is narrated by Bert Vogelstein (who showed in 1989 that p53 was a tumor suppressor gene), demonstrates another possible mechanism for fighting cancer. An adenovirus is used as a vector to deliver a DNA sequence to the cell's nucleus, allowing the virus to replicate. A normal cell with the wild-type p53 will suppress the expression this viral DNA. A transformed, or cancerous cell with a mutated and defective p53 gene will not be able to stop replication of the viral DNA which will not only cause death of the cell, but will also produce many more virus particles that can infect other cells.

Here's another video which shows the basic mechanism of how the p53 protein promotes transcription of a gene, presumably to induce apoptosis.

PNC-28: a p53 peptide for attacking the cancer cells through membrane disruption

I met with Dr Matthew Pincus, my mentor from the clinical pathology days, to discuss his latest publication in the Int. J. Cancer (2006) about a novel method for an anti-cancer therapy. You can read a press release describing this article at the SUNY Downstate Web site, and you can read the abstract which was published online in May of last year at Wiley Interscience.

Essentially, his team found that the peptide PNC-28 killed "a variety of human tumor cell lines," and a ras-transformed rat pancreatic carcinoma cell line, but had no effect on untransformed (normal) cell lines.

Now, allow me to provide the backstory to how this potential cancer therapy was discovered which you won't read in the journal article.

The image shows the molecular model of PNC-28, a peptide derived from p53, the protein which plays several important roles in acting as a tumor suppressor. These roles include activating DNA repair proteins when DNA damage has occurred, arresting the cell cycle at G1/S point so that repair can take place, and/or initiate apoptosis (cell death) in the case where the DNA damage cannot repaired.

In designing this peptide, Dr Pincus told me that the original intent was to target ubiquitin ligase, an enzyme which normally degrades p53. The idea was to do this by producing a peptide that was similar to the mdm-2-binding region of p53. Mdm-2, or hdm-2 in humans, inhibits the action of p53 and allows it to move from the cell's nucleus to the cytosol where it undergoes proteolysis by the ubiquitination. Blocking the mdm-2 interaction with p53 with PNC-28 should prolong the half-life of wild-type p53.

His rational design efforts were aimed at placing p53's penetratin part (this allows it to penetrate cell membranes) at the carboxy-terminal (C-terminal) end of of the PNC-28 peptide. The reason for this site and not the N-terminal of the peptide was to utilize the predominant positive charges at the C-terminal to stabilize the alpha helices. This was to preserve the peptide folding seen in the x-ray crystallography of p53 binding to mdm-2. (PNC-28 with the penetratin part at the N-terminal was also produced and tested, but it was not as effective on tumor cell lines.)

"We had the right answer using the wrong logic," said Dr Pincus when he described how the structure of PNC-28 might contribute to its role as a therapeutic agent. The positive charges at the C-terminal actually stabilized a helix-loop-helix structure which is amphipathic (containing polar and non-polar domains, somewhat in the way soap works), and therefore can exist within the lipid bilayer of the cell membrane. When this agent worked in a human tumor cell line that had a homozygous deletion of p53, this suggested that the action of PNC-28 had nothing to do with blocking the binding of mdm-2 to p53. Plus, when tests were done to check for markers of apoptosis, they weren't there. PNC-28 was causing necrosis, but not apoptosis of the tumor cell lines. This is believed to be accomplished through cell membrane disruption, perhaps analogous to the way the membrane attack complex of complement works. However, again, PNC-28 has no effect on untransformed cells, and no effect on the differentiation of human stem cells.

Why the predilection for cancer cells, then?