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Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts by MaverickNY

Whole genome sequencing and personalized medicine

By on April 20, 2011

Two articles and an accompanying editorial published in the Journal of the American Medical Association (JAMA) today look at whole genome sequencing in a small number of cancer patients with Acute Myeloid Leukemia (AML) and Acute Promyelocytic Leukemia (APL) to determine what mutations had developed and whether that knowledge would aid in clinical decision making.

In the case of one of the patients, the information learned from the sequencing led to a change in treatment, but sadly the AML patient died soon after.

There is a big caveat here – whole genome sequencing is not yet ready for prime time – the technique currently costs in the range of $20-40K per person, but in the future as costs come down, the $1K genome should be a viable goal to aid oncologists make clinical decisions through a more personalised medicine approach.  By that, I mean selecting a patient’s therapy based on the underlying molecular biology of their cancer – an individual thumbprint, if you like.

In the case of Welch et al’s, (2011) study, they wanted to see if sequencing could be taken out of the lab and into the clinical arena.  They had a particularly challenging case – a woman with a family history of cancer who was diagnosed with early onset breast and ovarian cancers in her thirties and unfortunately developed treatment-related AML (t-AML) and sadly died soon after.

The question here is what factor(s) might contribute to the cancer susceptibility?

BRCA1 and 2 analysis was not particularly useful in this case.  However, whole genome sequencing from the skin and leukemic cells identified a new TP53 mutation – essentially the technique picked up unknown structural variants that are missed by conventional assays.  As Pasche and Absher summarised it in their editorial:

“The patient was heterozygous for a novel deletion of 3 exons of the TP53 gene and that the intact copy of TP53 had been lost in the leukemic cells due to uniparental disomy.

This mutation in TP53 would not have been discovered without whole-genome sequencing.”

This finding also has important implications for the offspring of carriers of this mutation.

Link et al’s (2011) study was a little different.  They also had a challenging case – a patient diagnosed and being treated for AML who was awaiting an allogeneic stem cell transplant.  The pre-treatment bone marrow cells were used for the whole genome sequencing.

The sequencing results produced a surprise from the analysis – they revealed the presenece of a novel and cytogenetically invisible fusion oncogene normally associated with APL, thus enabling the clinical team to reconsider a new treatment plan for the patient based on the differential diagnosis.

The editorial concluded that:

“Hence, recent advances in genomics are likely to change the molecular characterization of cancer rapidly and provide a path for the personalized treatment of patients with cancer.”

To which I would add the caveat that whole genome sequencing, while intuitively very useful, is unlikely to have a wider impact until sequencing costs come down to more sensible and practical levels.

However, this time is fast approaching since genome sequencing costs are beating Moore’s Law in the rate they are decreasing.  The research papers published in JAMA this week are an important milestone on the road to personalised medicine.

References:

ResearchBlogging.orgWelch, J., Westervelt, P., Ding, L., Larson, D., Klco, J., Kulkarni, S., Wallis, J., Chen, K., Payton, J., Fulton, R., Veizer, J., Schmidt, H., Vickery, T., Heath, S., Watson, M., Tomasson, M., Link, D., Graubert, T., DiPersio, J., Mardis, E., Ley, T., & Wilson, R. (2011). Use of Whole-Genome Sequencing to Diagnose a Cryptic Fusion Oncogene JAMA: The Journal of the American Medical Association, 305 (15), 1577-1584 DOI: 10.1001/jama.2011.497

Link, D., Schuettpelz, L., Shen, D., Wang, J., Walter, M., Kulkarni, S., Payton, J., Ivanovich, J., Goodfellow, P., Le Beau, M., Koboldt, D., Dooling, D., Fulton, R., Bender, R., Fulton, L., Delehaunty, K., Fronick, C., Appelbaum, E., Schmidt, H., Abbott, R., O’Laughlin, M., Chen, K., McLellan, M., Varghese, N., Nagarajan, R., Heath, S., Graubert, T., Ding, L., Ley, T., Zambetti, G., Wilson, R., & Mardis, E. (2011). Identification of a Novel TP53 Cancer Susceptibility Mutation Through Whole-Genome Sequencing of a Patient With Therapy-Related AML JAMA: The Journal of the American Medical Association, 305 (15), 1568-1576 DOI: 10.1001/jama.2011.473

Pasche, B., & Absher, D. (2011). Whole-Genome Sequencing: A Step Closer to Personalized Medicine JAMA: The Journal of the American Medical Association, 305 (15), 1596-1597 DOI: 10.1001/jama.2011.484

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GRIN2A gene may be a new target in metastatic melanoma

By on April 19, 2011

This is turning out to be quite a week for posts on interesting and new things happening in melanoma.

Source: Wikipedia: metastatic melanoma that has invaded the pancreas

Yesterday, we discussed novel mechanisms of resistance to BRAF inhibitors such as PLX4032 and tomorrow we will review new findings associated with MEK resistance, but today I wanted to draw your attention to more basic research, that is, the identification of a new mutation in melanoma.

In a fascinating Letter to Nature Genetics, Wei et al., (2011) described how they used exome sequencing to systematically look at alterations in the DNA seen in the disease in 14 matched normal and metastatic tumours:

“Using stringent criteria, we identified 68 genes that appeared to be somatically mutated at elevated frequency, many of which are not known to be genetically altered in tumors.”

This is crucial, because when we consider therapeutic intervention down the road, we want to find targets that are aberrant in cancer, but preferrably, do not exist in people without cancer.  The reason for this is that many unwanted side effects are reduced by having a clear and obvious target.

What did the research show?

According to Wei et al., (2011), they found

“We discovered that TRRAP harbored a recurrent mutation that clustered in one position (p. Ser722Phe) in 6 out of 167 affected individuals (~4%), as well as a previously unidentified gene, GRIN2A, which was mutated in 33% of melanoma samples.”

The emphasis is mine, but what I found interesting was that TRRAP may be a new oncogene and GRIN2A may offer a druggable target in the same way that BRAF currently does for BRAF inhibitors.

Now, there are some limitations to this excellent piece of research:

  1. Small sample size
  2. Extrapolation to a wider population cannot be assumed
  3. Further research is essential to validate the targets

Implications:

The limitations aside, the findings are very important and do provide some useful clues for researchers to home in on and consider new studies to advance both the field, and our understanding of the biology of melanoma, further:

“Our study provides… the most comprehensive map of genetic alterations in melanoma to date and suggests that the glutamate signaling pathway is involved in this disease.”

This may a little bit of a surprise to the uninitiated.  Glutamate is an essential amino acid and a transmitter in the mature mammalian nervous system, but glutamate antagonists have been shown to limit tumour growth, as you can see in a PNAS article from Rzeski et al., (2001).

Overall, I think we will be hearing more about TRRAP and GRIN2A in metastatic melanoma going forwards.

References:

ResearchBlogging.orgWei, X., Walia, V., Lin, J., Teer, J., Prickett, T., Gartner, J., Davis, S., Stemke-Hale, K., Davies, M., Gershenwald, J., Robinson, W., Robinson, S., Rosenberg, S., & Samuels, Y. (2011). Exome sequencing identifies GRIN2A as frequently mutated in melanoma Nature Genetics DOI: 10.1038/ng.810

Rzeski, W. (2001). From the Cover: Glutamate antagonists limit tumor growth Proceedings of the National Academy of Sciences, 98 (11), 6372-6377 DOI: 10.1073/pnas.091113598

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COT drives resistance to PLX4032 through MAPK reactivation

By on April 18, 2011

At the recent annual American Association for Cancer Research (AACR) meeting, Keith Flaherty from Mass General Hospital discussed the latest developments in metastatic melanoma in a plenary session.

Much of the talk focused on progress to date with existing therapies, new mechanisms of resistance in BRAF V600E driven melanoma relating to COT, based on a recent Nature publication at the end of last year (see references below) and the potential for new compounds in the pipeline.

Remember that BRAF mutations are expressed in only 7% of cancers, but 60% of melanomas and mutant BRAF was seen as a poor prognostic factor until PLX4032 (now known as vemurafenib) came along and achieved some starting results in some patients.

Many of you may recall that we discussed other mechanisms of resistance to PLX4032. You can see in the kinase pathway how COT connects with RAF, so it is not entirely surprising to see an adaptive pathway emerge at this point.

Essentially, what happened is that the scientists looked for possible mechanisms of resistance that may offer new druggable targets to overcome BRAF resistance.  The Nature Letter is quite technical, but makes for an interesting read for those familiar with kinase screens and cell lines:

“Here we expressed ~600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor.  We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines.”

They then went on to explain what they found from this approach:

“COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling.  Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors.”

The good news is that COT is a tyrosine kinase, which means in theory it offers a new druggable target for therapeutic intervention, thus we may see chemists busy working on producing new kinase inhibitors that target COT, thereby offering a new combination down the road for melanoma clinical trials.

In the meantime though, there are some other promising new compounds in the pipeline that I have been watching, making advanced melanoma very much a hot topic of late, especially as much of the progress is based on translational research running in parallel. This may well be the future in cancer research – moving from bench to bedside in a seamless and ever evolving cycle.  It also speaks to the value of involving more scientist-physicians in the process to ensure that the learnings are reincorporated into research quickly and efficiently.  We need more of this sort of approach elsewhere for rapid progress to be made!

New therapeutic developments

Looking at the clinical trials database, there are many other compounds in development for metastatic melanoma, so all hope is not lost if PLX4032 primary or secondary resistance sets in, since sequencing or combination of different agents may be important in order to delay the onset of drug resistance.

As Dr Flaherty noted in his plenary talk at AACR, the next generation of inhibitors will seek to build on the success of PLX4032, offering further improvements:

  1. Increased potency and/or selectivity for BRAF
  2. Pan-RAF inhibitors with increased potency against CRAF
  3. Dimerization blockers

Some examples of the immediate melanoma pipeline for kinase inhibitors include:

  1. GSK2118432 (GSK) is a selective BRAF inhibitor similar to PLX4032
  2. PLX4720 (Plexxikon) next generation BRAF inhibitor, targets BRAF and CRAF
  3. RAF265 (Novartis) targets both BRAF and CRAF
  4. XL281 (Exelixis) similarly targets BRAF and CRAF
  5. AZD6244 (AstraZeneca) a MEK inhibitor
  6. GSK1120212 (GSK) also inhibits MEK

You can see more detail from Dr Flaherty’s talk given at the Targeted Anticancer Therapies Conference in March (PDF link, open access), which is similar to the AACR plenary talk we heard in Orlando:

Targeting BRAF in metastatic melanoma

The advantage of combining BRAF and MEK inhibitors is that you get increased PARP & caspase 3 cleavage at lower concentrations, at least when tested with PLX4720, suggesting that this may be a useful approach if the results are reproduced clinically.

In addition, as we learn more about the biology of the disease, so out knowledge of the importance of related and adaptive pathways also increases.  These include many we have discussed on this blog in other tumour types previously, including AKT, PI3K-mTOR, CDK2 and CDK4 as Dr Flaherty showed in this elegant slide:

New potential combination therapies in metastatic melanoma

What next?

My take on all of this is that it’s good to see new combinations emerge to combat various mechanisms of resistance that are evolving, and perhaps potentially reduce the squamous proliferation seen in some patients with PLX4032 due to CRAF being activated.

Overall, it does look like metastatic melanoma will be a hot topic at ASCO if there are some exciting new mature data available for presentation and discussion.

References:

ResearchBlogging.orgJohannessen, C., Boehm, J., Kim, S., Thomas, S., Wardwell, L., Johnson, L., Emery, C., Stransky, N., Cogdill, A., Barretina, J., Caponigro, G., Hieronymus, H., Murray, R., Salehi-Ashtiani, K., Hill, D., Vidal, M., Zhao, J., Yang, X., Alkan, O., Kim, S., Harris, J., Wilson, C., Myer, V., Finan, P., Root, D., Roberts, T., Golub, T., Flaherty, K., Dummer, R., Weber, B., Sellers, W., Schlegel, R., Wargo, J., Hahn, W., & Garraway, L. (2010). COT drives resistance to RAF inhibition through MAP kinase pathway reactivation Nature, 468 (7326), 968-972 DOI: 10.1038/nature09627

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Hormonal therapy and cancer – the controversy rages on

By on April 15, 2011

Hormone replacement therapy (HRT) is one of those subjects where many have a strong opinion either way and I suspect even if we have another dozen trials evaluating at the pros and cons, those opinions won’t change very much.

That said, the latest large randomised, double blind, placebo controlled study from the Women’s Health Initiative (WHI) in postmenopausal women with a prior hysterectomy (n=10,739) taking conjugated equine estrogens (CEE) such as Premarin has just reported their health outcomes analysis.

The original goal of the trial was to examine health outcomes after a mean of 10.7 years of follow-up.  The study was stopped, however, after a mean of 7.1 years of follow-up because there was an increased risk of stroke. LaCroix et al., (2011) provided some context:

“The Women’s Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date. Postintervention health outcomes have not been reported.”

The baseline characteristics looked well balanced between the two arms, so I took a quick look at the hazard ratio plots to see which factors favoured placebo and noted not only stroke, but also deep vein vein thrombosis (DVT) and pulmonary embolism.  It was easy to see why the trial was stopped early based on those results, especially as there were no significant differences in statin or aspirin use between the two groups.

Interestingly, looking at the topline hazard ratios on the cancer side, invasive breast cancer was lower on the treatment side, but colorectal cancer was more favourable in the placebo arm.  Previous trials have shown an increase in treatment related breast cancers. Part of this reason may lie in the type of hormone treatments given (estrogens only versus combination therapy) and variations in the patient groups.  Of course, the news media instantly picked up on the cancer issue rather than the cardiovascular effects.

Things started to get interesting, however, as I noticed that in the abstract, LaCroix et al., (2011) clearly stated:

“Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality.  A decreased risk of breast cancer persisted.”

Eh?  That’s not what you see in the hazard ratio plots, so I went back to re-read the paper and discussion in more detail.

The differences can be explained in the long term follow-up after treatment:

“Among postmenopausal women with prior hysterectomy who stopped taking CEE after a median of 5.9 years of use, several patterns of health risks and benefits seen during the intervention period were not maintained during the postintervention period, while other trends persisted.”

In other words, you often lose an effect post treatment, which can be a good or bad thing depending upon the parameter itself.

With the stroke and cardiovascular events seen in the intervention period on treatment, for example, in the post intervention period those effects “rapidly dissipated” during the postintervention period.

No doubt we will see future subgroup analyses emerge from this trial, it would be interesting to see, for example, whether mammogram screening was higher in either group and whether that impacted the findings or not.  Certainly that has been suggested in the past as one reason for the higher incidence of breast cancer in HRT users in other studies – in other words if you got looking for it more often you may well find it.

That said, the HRT story is likely to run and run as will emotions and opinions.

For some different perspectives, I can highly recommend checking out blog posts on the subject from Medical Lessons for a physician’s take and Flash Free for a science writer’s thoughts.  There was also an insightful commentary (open access) in Cancer Prevention Research from Craig Jordan and Leslie Ford (see references), who noted:

“Administration of estrogen replacement therapy (ERT) to hysterectomized postmenopausal women decreases the incidences of breast cancer.  Though paradoxical because estrogen is recognized to stimulate breast cancer growth, laboratory data support a mechanism of estrogen-induced apoptosis under the correct environmental circumstances.”

Personally?  I wouldn’t take it and I’m too young anyway, but I would like to see more granular research on which subpopulations are most likely to benefit, something that is not really that clear even now.  I’ll leave you with a striking insight from Jordan and Ford:

“The important issue for the decision of breast cancer cells to survive or die in response to estradiol depends entirely on the cell populations present in an estrogenized environment or following estrogen deprivation.”

Maybe we need more cowbell.

References:

This post was chosen as an Editor's Selection for ResearchBlogging.orgLaCroix AZ, Chlebowski RT, Manson JE, Aragaki AK, Johnson KC, Martin L, Margolis KL, Stefanick ML, Brzyski R, Curb JD, Howard BV, Lewis CE, Wactawski-Wende J, & WHI Investigators (2011). Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA : the journal of the American Medical Association, 305 (13), 1305-14 PMID: 21467283

Jungheim ES, & Colditz GA (2011). Short-term use of unopposed estrogen: a balance of inferred risks and benefits. JAMA : the journal of the American Medical Association, 305 (13), 1354-5 PMID: 21467291

Jordan, V., & Ford, L. (2011). Paradoxical Clinical Effect of Estrogen on Breast Cancer Risk: A “New” Biology of Estrogen-Induced Apoptosis Cancer Prevention Research DOI: 10.1158/1940-6207.CAPR-11-0185

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Biology of indolent B-cell lymphomas and chronic lymphocytic leukemia

By on April 14, 2011

We all know the importance that inflammation and the immune system plays in the early development of many cancers, but this is not a ubiquitous finding.  Indeed, some hematologic malignancies arise out of immunodeficiency, such as myelomas and chronic lymphocytic leukemia (CLL).  I haven’t written much about this topic in the past, so thought it would be useful to explain some of the underlying biology of CLL given that we can expect new (hopefully positive) data emerge at the American Society of Clinical Oncology (ASCO) meeting in June.

Several studies have shown specifically that immune activation can promote development and progression of lymphoma.  Extranodal marginal zone lymphomas (eMZLs), for example, originate at the site of chronic inflammation under the influence of T-cell help (see Suarez et al., 2006).

Hervé et al., (2005) have previously shown that antigen receptor repertoires exist in B-cell lymphoma and additionally, autoantigen recognition by CLL-derived immunoglobulin may suggest a role for antigen receptor signaling in lymphomagenesis.

In addition, an increase in circulating regulatory T cells (Tregs) has been reported in myeloma, CLL, and other B-cell lymphomas by Breyer et al., (2005) and confirmed by others.  This may well explain why the combination of fludarabine and cyclophosphamide (FC) is a useful strategy in reducing immunosuppression prior to cancer immunotherapy with rituximab (R).  The FCR combination is now very much the bedrock of treatment for patients with CLL and is based on a very solid rationale.

Previous work in 2004 by Christopoulos et al., observed a significant reduction in peripheral T helper cells in patients with untreated FL and eMZL.  The question remains as to what happens to the T-helper cells in untreated CD4+ subpopulations.

Christopoulos et al., (2011) therefore conducted a prospective open label study recently to look at the underlying immune system in patients with CLL or monoclonal gammopathy of unknown significance (MGUS).  According to the Mayo Clinic:

“Monoclonal gammopathy of undetermined significance (MGUS) is a condition in which an abnormal protein (monoclonal protein, or M protein) is in the blood.”

In terms of the selection criteria, patients with prior antineoplastic therapy, including corticosteroids, and patients with evidence for preexisting autoimmunity or immunodeficiency were excluded from the study.

The current study is interesting, because the results demonstrated:

“substantially reduced circulating T helper cells, predominantly naive CD4+ cells, in patients with nonleukemic follicular lymphoma and extranodal marginal zone lymphoma, but not in monoclonal gammopathy and early CLL.”

They went to to say that:

“Gene expression profiling of in vitro–stimulated CD4+ cells revealed an independent second alteration of T helper cell physiology, which was most pronounced in early CLL but also detectable in follicular lymphoma/extranodal marginal zone lymphoma.”

What new therapies are emerging for CLL?

Rituximab has been a very useful addition to the basic FC regimen in CLL.  A number of other therapies are also being evaluated in the disease, including fostamatinib, a SYK inhibitor from AstraZeneca and lenalidomide, a widely used immunotherapy for the treatment of multiple myeloma from Celgene.

Friedberg et al., (2010) published their data on fostamatinib in CLL and NHL last year based on the promising results previously presented at ASCO in 2009.  I wrote about the data at that meeting here for those interested.  Lenalidomide is being evaluated as a maintenance therapy for CLL in clinical trials (see my notes on the previous data presented at ASH) and given it is now 18 months to two years since we saw the initial data, I’m hoping there will be an update in Chicago this year, including some information on the optimal lenalidomide dose (see Wendtner et al., 2010).

Although CLL is a relatively indolent disease, patients can cycle through multiple therapies and combinations over time, so there is still a need for new drugs to mix up the combinations and extend life for this chronic condition further.

A future update will appear on this topic at ASCO in June – watch this space!

References:

ResearchBlogging.orgChristopoulos, P., Pfeifer, D., Bartholome, K., Follo, M., Timmer, J., Fisch, P., & Veelken, H. (2011).  Definition and characterization of the systemic T-cell dysregulation in untreated indolent B-cell lymphoma and very early CLL Blood, 117 (14), 3836-3846 DOI: 10.1182/blood-2010-07-299321

Suarez F, Lortholary O, Hermine O, & Lecuit M (2006). Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation. Blood, 107 (8), 3034-44 PMID: 16397126

Hervé M, Xu K, Ng YS, Wardemann H, Albesiano E, Messmer BT, Chiorazzi N, & Meffre E (2005). Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity. The Journal of clinical investigation, 115 (6), 1636-43 PMID: 15902303

Christopoulos P, Follo M, Fisch P, & Veelken H (2008). The peripheral helper T-cell repertoire in untreated indolent B-cell lymphomas: evidence for antigen-driven lymphomagenesis. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K, 22 (10), 1952-4 PMID: 18385751

Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, Schaefer-Cutillo J, De Vos S, Sinha R, Leonard JP, Cripe LD, Gregory SA, Sterba MP, Lowe AM, Levy R, & Shipp MA (2010). Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood, 115 (13), 2578-85 PMID: 19965662

Wendtner CM (2011). Lenalidomide in CLL: What Is the Optimal Dose? Clinical advances in hematology & oncology : H&O, 9 (3), 220-4 PMID: 21475128

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GWAS and breast cancer metastases

By on April 13, 2011

Breast cancer isn’t a topic I cover very often on this blog, mainly because there is so much written about it elsewhere, but I confess to being fascinated by the ongoing work on cancer cell seeding and metastases from Joan Massague and Larry Norton at Memorial Sloan Kettering.   The reason for this is that the origins of metastases might have wider applicability to other cancers, so the studies as a body of work are important in the field.   For those of you looking for some background on this important topic, check out this previous post on cancer cell seeding first.

Unfortunately, while at AACR the other week I lost track of time in the huge poster session one morning and missed Joan Massague’s plenary talk, but hopefully it will be available on the webcasts later this month, and I will post another update then.

Where are we now?

Science Translational Medicine

In the latest research, published last month in Science Translational Medicine, the researchers used Genome-Wide Analysis Studies (GWAS) to look at methylome signatures in breast cancers to see if there was any correlation between different patterns and survival.

We know that widespread changes in DNA methylation patterns occur during oncogenesis and tumour progression, so detailed research using GWAS may help us uncover patterns that ultimately help us unravel the heterogeneity of the disease.   The more homogenous the subgroups, the greater the chances of successful treatment and improved outcomes for patients down the road.

To this end, samples from breast cancer tumours (discovery set, n=39; validation set, n=132) were gathered from patients at MSKCC and analysed.

What did they find?

In the current study, Fang et al., (2011) noticed that one pattern in particular was associated with low metastatic risk and hence improved survival, ie the breast CpG island methylator phenotype (B-CIMP).  The paper is well worth checking out for the survival curves of B-CIMP+ vs. B-CIMP- alone.  Beautiful.

Interestingly, this trend was independent of other known breast cancer markers including estrogen receptor/progesterone receptor (ER/PR) and human epidermal growth factor receptor 2 (HER2) status.  They also found similar results i.e. presence of B-CIMP genes in other human tumour types, including glioma and colon cancer, which are widely available in the Cancer Genome Atlas.

What do these findings mean?

There are several important findings that emerge from this work.

  1. Discovery of a global B-CIMP gene that is associated with improved survival helps identify a group of patients who are likely to do better
  2. B-CIMP phenotype may play a mechanistic role in metastatic risk
  3. Presence of B-CIMP across multiple tumour types suggests that it targets the same genes across different cancers

The authors concluded that:

“Our findings may enable the development of new molecular diagnostics that more accurately reflect the epigenomic underpinnings of breast cancer prognosis.  These diagnostics may help further refine our ability to implement personalized medicine for breast cancer patients.”

If that scenario happens, it will be an amazing discovery in the development of breast cancer research and treatment and may spur further innovation through improved targeted agents, diagnostics and patient selection.

References:

ResearchBlogging.orgFang, F., Turcan, S., Rimner, A., Kaufman, A., Giri, D., Morris, L., Shen, R., Seshan, V., Mo, Q., Heguy, A., Baylin, S., Ahuja, N., Viale, A., Massague, J., Norton, L., Vahdat, L., Moynahan, M., & Chan, T. (2011). Breast Cancer Methylomes Establish an Epigenomic Foundation for Metastasis Science Translational Medicine, 3 (75), 75-75 DOI: 10.1126/scitranslmed.3001875

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New mechanisms of resistance to MET inhibition

By on April 12, 2011

A very apt quote from Jeff Engelman’s group caught my eye this week:

“Unfortunately, cancers invariably develop resistance, and overcoming or preventing resistance will ultimately be key to unleashing their full therapeutic potential.”

MET is the receptor tyrosine kinase for hepatocyte growth factors (HGF) and inhibition has been implicated in metastases and migration of cancer cells (Rong et al., (1994), Takayama et al., (1997)), but more recently, it has also been observed that some tumour types have MET oncogenic addiction, including gastric cancer (Smolen et al., 2006).

MET Inhibition - source: Ma et al., (2007) BJC

Qi et al., (2011) went on to explain how they were looking at strategies for overcoming resistance to MET inhibitors, using PHA-665752 and PF-2341066, as an example in highly sensitive gastric cell lines.  They investigated the possibilities in vivo and in vitro. The results, however, were unexpected:

“To our surprise, we observed at least two mechanisms of resistance that arose simultaneously.  Both resulted in maintenance of downstream PI3K (phosphoinositide 3-kinase)-AKT and MEK (MAP/ERK kinase)-ERK signaling in the presence of inhibitor.”

Many of you will be aware of activation loops from other kinases, such as imatinib (Gleevec) in CML (T315I) and GIST (D842V) or erlotinib (Tarceva) in lung cancer (T790M), and adaptive pathways e.g. with BRAF inhibitors such as PLX4032 (vemurafenib) in melanoma, so this phenomenon is not uncommon.

With the MET inhibitors tested in the current research, the group found:

  1. A mutation in the MET activation loop, Y1230
  2. Activation of the epidermal growth factor receptor (EGFR) pathway due to increased expression of transforming growth factor alpha (TGFa)

What do these results mean?

The data suggests that combining MET and EGFR inhibitors in gastric cancer may be a viable therapeutic strategy, but consideration must also be given to approaches that inhibit Y1230 mutant MET as well, in order to shut off the escape routes.

It is hard to argue with the authors conclusion that:

“These results also underscore the notion that a single cancer can simultaneously develop resistance induced by several mechanisms and highlight the daunting challenges associated with preventing or overcoming resistance.”

Given the positive results seen with trastuzumab (Herceptin) in patients with HER2-positive gastric cancer, part of me is also wondering what incremental value there would be efficacy-wise, if MET and EGFR inhibitors were used in combination with trastuzumab?  We know that the blocking the driver mutation, the adaptive pathway and the ligand is important.  Some further preclinical research in this area may shed light on the matter.

References:

ResearchBlogging.orgQi, J., McTigue, M., Rogers, A., Lifshits, E., Christensen, J., Janne, P., & Engelman, J. (2011). Multiple Mutations and Bypass Mechanisms Can Contribute to Development of Acquired Resistance to MET Inhibitors Cancer Research, 71 (3), 1081-1091 DOI: 10.1158/0008-5472.CAN-10-1623

Ma, P., Tretiakova, M., Nallasura, V., Jagadeeswaran, R., Husain, A., & Salgia, R. (2007). Downstream signalling and specific inhibition of c-MET/HGF pathway in small cell lung cancer: implications for tumour invasion British Journal of Cancer, 97 (3), 368-377 DOI: 10.1038/sj.bjc.6603884

Rong S, Segal S, Anver M, Resau JH, & Vande Woude GF (1994). Invasiveness and metastasis of NIH 3T3 cells induced by Met-hepatocyte growth factor/scatter factor autocrine stimulation. Proceedings of the National Academy of Sciences of the United States of America, 91 (11), 4731-5 PMID: 8197126

Takayama H, LaRochelle WJ, Sharp R, Otsuka T, Kriebel P, Anver M, Aaronson SA, & Merlino G (1997). Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor. Proceedings of the National Academy of Sciences of the United States of America, 94 (2), 701-6 PMID: 9012848

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My AACR Poster of the Day

By on April 4, 2011

Yesterday heralded was the first of six four-hour poster sessions here at the American Association for Cancer Research (AACR) meeting.   Nearly 5,000 posters are being presented here in total, which makes for a lot of shoe leather running round the vast exhibit hall!

As my colleague pointed out on Biotech Strategy Blog, choosing one out of many interesting ones is a highly subjective matter.  He chose one on nanotechnology, an area that he has a keen interest in.

My selection for Poster of the Day is perhaps a little unusual.   In the patient advocacy session, Leslie Hammersmith’s stood out as a brilliant example of how to use social media really well at a scientific meeting.

What did I like about her approach?

1) She used Twitter to let people know she was presenting and drew attention to scientists like me to check out the poster (good marketing!).

2) The poster is simply and elegantly designed, making it easy to read for tired eyes, as mine were after a very long day.

3) The use of QR codes for references and supporting materials as well as a card handed out to enable downloading of the poster via a QR code was novel and interesting.

4) Loved the title: “Poke, Tweet, Tag, Share: A new generation of Cancer Advocacy”

The clever use of QR codes made me want it on all the science posters too, both for easy downloads instead of handouts, and links to references.   In terms of innovation and creativity, this poster won hands down for me.  Nice job, Leslie!

For those of you hankering to see the poster yourselves, check out the card below using your QR reader and see for yourself:

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Highlights of AACR – Day 2

By on April 4, 2011

Here at the American Association for Cancer Research (AACR) meeting, Day 2 brought us a packed Plenary session in a huge hangar of a hall. It was at this point I realised this is now a much much bigger meeting than I remember in the past, with an enormous variety of sessions and symposia, many running concurrently.

http://www.youtube.com/watch?v=Ogb0hbm7L8c

AACR are doing a great job posting full podcasts and webcasts of the event for those who couldn’t attend. The Varmus podcast is now live, for example. There is also one with Dr Ervin Epstein on the Hedgehog inhibitor I mentioned in basal cell nevus syndrome.

The full list of currently live podcasts have been posted by AACR. Do check it out as they post new content daily.

In case you are wondering, there is also a short video of the Day 1 highlights on Sat for those of you who are interested.

I won’t be posting a video tomorrow morning due to a commitment tonight to attend the inaugural #AACR tweetup organised by Angela Alexander (@flutesUD), a cancer researcher at MD Anderson whose work is focused on ATM. She is an up and coming scientist who recently won the PNAS Cozzarelli Prize for the top paper in biological sciences. If anyone is around at AACR and using Twitter, you are most welcome to just the motley crew at the Tweetup at the Peabody fountain bar around 6-8.30pm. A mixed group of scientists, patient advocates, clinicians, bloggers and biotech people are expected!

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Highlights of AACR – Day 1

By on April 3, 2011

Yesterday was a travel day for many of us at AACR and the weather doesn’t always cooperate in ensuring timely arrivals.  Never fear, there are ways to catch up on what was missed…. wondering what was hot on Day 1?  Check out the short video clip below:

http://www.youtube.com/watch?v=JS8ycFmI9x0

AACR have posted their webcast and podcasts links for those following remotely that are worth checking out – many are free as well, making them great value.

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