Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts by MaverickNY

Glioblastoma recurrence after VEGF therapy: lack of rebound vascularisation as a mode of escape

By on January 3, 2011

One of my favourite journals, Cancer Research, has a new paper available via open access (i.e. free to the public, thank you AACR), which you can obtain from the link in the Reference section below.

It caught my attention because there was a fascinating symposium on angiogenesis at ESMO this summer with some heavyweight debates from Robert Kerbel (accelerated metastasis) and Lee Ellis (normalisation of tumour vessels) taking different viewpoints on the pros and cons of VEGF inhibition.  I took a few photos of the slides for private study and reflection, as they were going too fast for me to keep up with the key points with unreadable chicken scratch notes, but sadly my iPhone went missing in the exhibit hall less than an hour afterwards before I could download the photos :(.  That said, both sides argued with very compelling data for their perspective that I’m not sure which way I roll on the issue.

In this latest paper, di Tomaso et al., from Boston discuss the concept of recurrent glioblastomas and the tendency to relapse after VEGF therapy.  They noted that there are two current theories for how this might happen:

  1. Switch to VEGF-independent angiogenic pathways
  2. Vessel co-option

They therefore decided to investigate these mechanisms in patients with relapsed glioblastoma using a pan VEGF inhibitor, cediranib.  Now, it should be noted that cediranib (Recentin) is not yet approved and is a small molecule inhibitor, whereas another VEGF inhibitor, bevacizumab (Avastin), is a monoclonal antibody approved for relapsed GBM, so I’m sure why they didn’t use that instead.  It does make extrapolation of the findings a little more tricky though, as you cannot always assume a class effect.

Here are the key findings:

  • Endothelial proliferation and glomeruloid vessels were decreased
  • Vessel diameters and perimeters were reduced to levels comparable to the unaffected contralateral brain hemisphere
  • Tumour endothelial cells expressed molecular markers specific to the blood–brain barrier, indicative of a lack of revascularization despite the discontinuation of therapy
  • Cellular density in the central area of the tumour was lower than in control cases and gradually decreased toward the infiltrating edge, indicative of a change in growth pattern of relapsed GBM after cediranib treatment
  • Cediranib-treated GBMs showed high levels of PDGF-C (platelet-derived growth factor C) and c-Met expression and infiltration by myeloid cells, which may potentially contribute to resistance to anti-VEGF therapy

The authors therefore concluded that:

“rGBMs switch their growth pattern after anti-VEGF therapy—characterized by lower tumor cellularity in the central area, decreased pseudopalisading necrosis, and blood vessels with normal molecular expression and morphology—without a second wave of angiogenesis.”

Commentary:

What intrigued me in particular was not the lack of rebound vascularisation effect but the myeloid component.  Many of you will remember the AACR meeting last September on Molecular Diagnostics in Cancer Therapeutics, where AVEO presented data on their VEGF inhibitor in development and found that the myeloid component acted as a useful biomarker of response for tivozanib in renal cell cancer. You can read more about that here if you missed it.

This raises several interesting questions for me:

  1. Is the myeloid marker that AVEO found with tivozanib actually more useful and applicable to VEGF therapies in general?
  2. Does the myeloid component indicate acute inflammation, as we have seen with respiratory and other diseases?
  3. If PDGF and MET expression rise as resistance sets in, does that suggest logical combination therapies for the treatment of GBM?
  4. How can we better overcome the blood brain barrier, which is a physical impediment to improving outcomes.

Time will tell but clearly the research in relapsed GBM has a-ways to go before we figure out how best to approach it yet.

References:

ResearchBlogging.org di Tomaso, E., Snuderl, M., Kamoun, W., Duda, D., Auluck, P., Fazlollahi, L., Andronesi, O., Frosch, M., Wen, P., Plotkin, S., Hedley-Whyte, E., Sorensen, A., Batchelor, T., & Jain, R. (2011). Glioblastoma Recurrence after Cediranib Therapy in Patients: Lack of “Rebound” Revascularization as Mode of Escape Cancer Research, 71 (1), 19-28 DOI: 10.1158/0008-5472.CAN-10-2602

Update on circulating tumor cells in colorectal cancer

By on December 28, 2010

Earlier this year we discussed some interesting papers on circulating tumour cells (CTC’s) in prostate cancer and how they are becoming a potentially useful surrogate marker in clinical trials for other cancers including lung cancer.

I was therefore intriqued to see another paper looking at the role of CTC’s in colorectal cancer (CRC) – see link below in the reference section at end of the article:

“Circulating tumour cells early predict progression-free and overall survival in advanced colorectal cancer patients treated with chemotherapy and targeted agents”

One of the challenges with some targeted therapies such as bevacizumab (Avastin) now routinely used for treatment of metastatic colorectal cancer is that while they improve overall survival, not all patients will actually respond to treatment.

While several studies have shown that the KRAS mutation status predicts response to EGFR therapy such as cetuximab (Erbitux) and panitumumab (Vectibix) in colorectal cancer, there is no known equivalent biomarker for determining who is most likely to respond to VEGF therapy with bevacizumab.

This situation creates a dilemma for the medical oncologist, because other than excluding those patients most at risk from the side effects (patients with cardiovascular disease, hypertension etc), perhaps 1 in five of the advanced CRC patients, there is no way to determine which of the remaining 4/5 people will respond, thus potentially exposing all to the not insignificant systemic effects of the drug with no idea who might be an ideal candidate.

Previously, research from Cohen et al., has shown in advanced CRC that the CTC at baseline and during treatment were prognostic for OS and PFS (see references below). These studies included a broad heterogeneous population of untreated and pre-treated patients who received different schedules of treatment, making it difficult to draw specific conclusions.  That said, the research demonstrated that the technique is useful and can be measured from blood samples while not requiring invasive biopsies.

In this article, the researchers decided to see whether CRC’s would be a useful tool for predicting the responders from non-responders better in a more homogenous population.

What did the results show?

Perhaps the most interesting quote in this journal article was the finding that:

“The combined analysis of CTC and CT imaging provided a more accurate outcome assessment than either modality alone.”

Clearly, RECIST measurements are not going to go away, but combining the data with newer biomarker analysis that reflects the underlying biology may well be a good compromise.

What does this all mean?

Historically, physicians have used pathologic measures of measuring tumour response using RECIST criteria, but the problem with this approach is that tumour shrinkage alone does not always translate into an improvement in meaningful outcome for the patient. Sometimes patients can have no shrinkage and stable disease but still a reasonable and functional quality of life, as happens with some soft tissue sarcomas, for example.

New surrogate markers of survival are therefore needed that also tell us something about about the risk of recurrence.   This new paper provides additional evidence that:

“The CTC count before and during treatment independently predicts PFS and OS in ACC patients treated with chemotherapy plus targeted agents and provides additional information to CT imaging.”

They based this conclusion on the results that demonstrated:

“The sensitivity and specificity of high CTC at baseline for the prediction of progressive disease on CT imaging were 16.7% and 70.1%, respectively, and of high CTC at 1–2 weeks after the start of treatment 20.0% and 95.1%, respectively.”

They also went on to note that:

“We demonstrate that CTC counts identify a small group of patients with unfavourable outcome early during treatment. However, whether a change in treatment on the basis of CTC count will result in a better survival for this group is yet unknown, and this issue should be addressed in a prospective trial.  In such a design, it will also be worthwhile to investigate the cost-effectiveness of CTC testing.”

Unfortunately, although a reasonably large number patients were evaluated (n=467) in this study, half were treated with capecitabine, oxaliplatin, and bevacizumab and half received the same regimen plus weekly cetuximab, but the results were oddly described in the aggregate.  We therefore have no idea whether CTC’s were more useful in the bevacizumab only arm, or when cetuximab was added.  We do know that in the patients who did poorly, although their specific treatment is not described, they did have high CTC levels and poor disease control.

CTC’s are something we will likely hear a lot more about in research going forward from a biomarker perspective though, as researchers begin to incorporate their measurement into the design of more clinical trials.

References:

ResearchBlogging.orgTol, J., Koopman, M., Miller, M., Tibbe, A., Cats, A., Creemers, G., Vos, A., Nagtegaal, I., Terstappen, L., & Punt, C. (2009). Circulating tumour cells early predict progression-free and overall survival in advanced colorectal cancer patients treated with chemotherapy and targeted agents Annals of Oncology, 21 (5), 1006-1012 DOI: 10.1093/annonc/mdp463

Cohen, S., Punt, C., Iannotti, N., Saidman, B., Sabbath, K., Gabrail, N., Picus, J., Morse, M., Mitchell, E., Miller, M., Doyle, G., Tissing, H., Terstappen, L., & Meropol, N. (2009). Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer Annals of Oncology, 20 (7), 1223-1229 DOI: 10.1093/annonc/mdn786

Cohen, S., Punt, C., Iannotti, N., Saidman, B., Sabbath, K., Gabrail, N., Picus, J., Morse, M., Mitchell, E., Miller, M., Doyle, G., Tissing, H., Terstappen, L., & Meropol, N. (2008). Relationship of Circulating Tumor Cells to Tumor Response, Progression-Free Survival, and Overall Survival in Patients With Metastatic Colorectal Cancer Journal of Clinical Oncology, 26 (19), 3213-3221 DOI: 10.1200/JCO.2007.15.8923

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Six feet under – snowpocalypse 2010

By on December 27, 2010

Maybe two feet under snow really, judging by my back yard, which is largely sheltered and not prone to drifts. It looks like a pristine Winter Wonderland.

For once, the weathermen were right when they said a blizzard was coming.  Twitter and Foursquare are abuzz with people signing in or tweeting about #snowpocalypse2010, #snomageddon or #snomg in jest, but really it’s just a lot of noise about the first snowfall of the season.

The result out front on the street is a big mess though, as the howling wind, drifting snow and snow ploughs have created huge 6ft ridges behind which are parked cars in igloo like humps.  Glad I parked on the left hand side to avoid that conundrum 😉

Still, there is a good two feet plus on the path and pavement, so shovelling it all will be the highest priority today.

Wherever you all are in the world, stay warm and dry.  I’ll leave you with an old post on the ipilimumab data to contemplate some thoughts, since this will be a hot topic of discussion in January with the FDA ODAC meeting scheduled for the beginning of Feb.

It will also soon be time for the annual year in review for 2010 and predictions for 2011 posts coming up.  What were your big events in cancer this year?  Do let me know if you have any predictions for next year in the comments below.

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Seasons Greetings from Pharma Strategy Blog!

By on December 24, 2010

HOLIDAY EATING TIPS (In case you forgot!)

A big Hat Tip to my buddy Samy for these… ‘Tis the Season of Joy:

1. Avoid carrot sticks.  Anyone who puts carrots on a holiday buffet
table knows nothing of the Holiday spirit.  In fact, if you see carrots,
leave immediately.  Go next door, where they’re serving rum balls.

2. Drink as much eggnog as you can.  And quickly.  It’s rare.  You cannot
find it any other time of year but now.  So drink up!  Who cares that it
has 10,000 calories in every sip?  It’s not as if you’re going to turn
into an eggnog-alcoholic or something.  It’s a treat.  Enjoy it.  Have one
for me.  Have two.  It’s later than you think.  It will soon be Christmas!

3. If something comes with gravy, use it.  That’s the whole point of
gravy.  Gravy does not stand alone.  Pour it on.  Make a volcano out of
your mashed potatoes.  Fill it with gravy.  Eat the volcano.  Repeat.

4. As for mashed potatoes, always ask if they’re made with skim milk or
whole milk.  If it’s skim, pass.  Why bother?  It’s like buying a sports
car with an automatic transmission.

5. Do not have a snack before going to a party in an effort to control
your eating.  The whole point of going to a Holiday party is to eat
other people’s food for free.  Lots of it. Hello?

6. Under no circumstances should you exercise between now and New
Year’s.  You can do that in January when you have nothing else to do.
This is the time for long naps, which you’ll need after circling the
buffet table while carrying a 10-pound plate of food and that vat of
eggnog.

7. If you come across something really good at a buffet table, like
frosted Christmas cookies in the shape and size of Santa, position
yourself near them and don’t budge.  Have as many as you can before
becoming the center of attention.  They’re like a beautiful pair of
shoes.  If you leave them behind, you’re never going to see them again.

8. Same for pies. Apple, Pumpkin, Mincemeat. Have a slice of each. Or if
you don’t like mincemeat, have two apples and one pumpkin.  Always have
three.  When else do you get to have more than one dessert? Labor Day?

9. Did someone mention fruitcake? Granted, it’s loaded with the
mandatory celebratory calories, but avoid it at all cost.  I mean,
please, have some standards!

10. One final tip: Wear sweatpants/loose fitting clothing. If you are
leaving the party and you can walk without help from a construction
forklift, “you haven’t been paying attention, people!” Re-read tips;
start over, but hurry, January is just around the corner.  Remember this
motto to live by:

“Life should NOT be a journey to the grave with the intention of
arriving safely in an attractive and well preserved body, but rather to
skid in sideways, chocolate and wine in one hand, body thoroughly used
up, totally worn out and screaming “WOO HOO what a ride!”

Have a great holiday season!!

This year in lieu of the fancy Christmas cards we bought half price in January (and last year, and the year before that) but somehow can never find when we really need them, we donated a fist of silver to CancerGRACE in support of education for people with lung cancer.

Warmest wishes to y’all for a truly wonderful 2011.

DNMT3A Mutations in Acute Myeloid Leukemia – an update

By on December 21, 2010

The current New England Journal of Medicine has an in-depth article on DNMT3A Mutations in Acute Myeloid Leukemia (AML).   Many of you will remember the discussion on this topic last month based on the two case studies that the same authors covered in the journal, where the DNMT3A mutation was shown to be associated with a poorer prognosis.  They now offer an update to the story:

“We did not find new recurring mutations in the first study but did observe a recurrent mutation in IDH1, encoding isocitrate dehydrogenase 1, in the second study. Subsequent work has confirmed and extended this finding, showing that mutations in IDH1 and related gene IDH2 are highly recurrent in patients with an intermediate-risk cytogenetic profile (20 to 30% frequency) and are associated with a poor prognosis in some subgroups of patients.

Improvements in sequencing techniques prompted us to reevaluate the first case with deeper sequence coverage, during which we discovered a frameshift mutation in the DNA methyltransferase gene DNMT3A.”

DNMT1, DNMT3A, and DNMT3B are genes that encode DNA methyltransferases.   These are enzymes that catalyse the addition of a methyl group to the cytosine residue of CpG dinucleotides.  Clusters of CpG dinucleotides are concentrated in regions upstream of genes.   It is known that increased methylation of these CpG islands is often associated with reduced expression of the downstream gene.

Aberrant DNA methylation has long been hypothesized to contribute to the pathogenesis of cancer.  However, cancer genomes tend to be hypomethylated, but hypermethylation of CpG islands in the promoters of tumor-suppressor genes (TSG) is also common in many tumours.  DNA methyltransferase inhibitors are currently one available option for the treatment AML, and includes drugs such as decitabine and azacitidine.  The response rates are generally fairly low and unpredictable, however, because there is no biomarker available to determine which patients will most likely respond to therapy.

Given the differences in the two case studies, the next step was clear:

“After discovering a frameshift mutation in DNMT3A with whole-genome sequencing, we conducted a study to determine whether DNMT3A is recurrently mutated in AML samples and whether DNMT3A mutations are associated with poor survival.”

To give an idea of the sheer scale of the datasets that these kind of GWAS studies generate in one patient, I was fascinated to read the following:

“We previously sequenced the AML genome of a sample obtained from Patient 933124 and obtained short single-end reads, yielding 98 billion base pairs of sequence and 91.2% diploid coverage of the genome. In this study, we obtained 116.4 billion base pairs with paired-end reads from the genome of the relapsed tumor, yielding 99.6% diploid coverage of the genome.”

What did they find?

The survival results based on the Kaplan-Meier curves clearly showed that those AML patients with no DNMT3A mutation clearly had better survival than those who did have the mutation, regardless of age and FLT3 mutation status.  You can check out the curves in the reference below.

The authors concluded that:

“DNMT3A mutations are highly recurrent in patients with de novo AML with an intermediate-risk cytogenetic profile and are independently associated with a poor outcome.”

What these results mean in practice (for now), is that the DNMT3A mutation offers a way to classify intermediate risk AML and thus an indication for earlier, more intensive treatment such as allogeneic stem cell transplant. Whether the mutation is druggable or not for future therapeutic intervention isn’t clear yet.

References:

ResearchBlogging.org Ley, T., Ding, L., Walter, M., McLellan, M., Lamprecht, T., Larson, D., Kandoth, C., Payton, J., Baty, J., Welch, J., Harris, C., Lichti, C., Townsend, R., Fulton, R., Dooling, D., Koboldt, D., Schmidt, H., Zhang, Q., Osborne, J., Lin, L., O’Laughlin, M., McMichael, J., Delehaunty, K., McGrath, S., Fulton, L., Magrini, V., Vickery, T., Hundal, J., Cook, L., Conyers, J., Swift, G., Reed, J., Alldredge, P., Wylie, T., Walker, J., Kalicki, J., Watson, M., Heath, S., Shannon, W., Varghese, N., Nagarajan, R., Westervelt, P., Tomasson, M., Link, D., Graubert, T., DiPersio, J., Mardis, E., & Wilson, R. (2010).  Mutations in Acute Myeloid Leukemia.  New England Journal of Medicine, 363 (25), 2424-2433 DOI: 10.1056/NEJMoa1005143

Ley, T., Ding, L., Walter, M., McLellan, M., Lamprecht, T., Larson, D., Kandoth, C., Payton, J., Baty, J., Welch, J., Harris, C., Lichti, C., Townsend, R., Fulton, R., Dooling, D., Koboldt, D., Schmidt, H., Zhang, Q., Osborne, J., Lin, L., O’Laughlin, M., McMichael, J., Delehaunty, K., McGrath, S., Fulton, L., Magrini, V., Vickery, T., Hundal, J., Cook, L., Conyers, J., Swift, G., Reed, J., Alldredge, P., Wylie, T., Walker, J., Kalicki, J., Watson, M., Heath, S., Shannon, W., Varghese, N., Nagarajan, R., Westervelt, P., Tomasson, M., Link, D., Graubert, T., DiPersio, J., Mardis, E., & Wilson, R. (2010).
Mutations in Acute Myeloid Leukemia New England Journal of Medicine DOI: 10.1056/NEJMoa1005143

$JNJ files NDA for abiraterone in castration resistant prostate cancer

By on December 20, 2010

At the recent European Society of Medical Oncology (ESMO) meeting, J&J and Centocor OrthoBiotech announced that they planned to submit the filing for abiraterone by the year end, following the presentation of the phase III data by Johann de Bono from the Royal Marsden.  That moment finally came today with a press release announcing the news within the last half hour or so.

The filing, in castration resistant prostate cancer (CRPC) after treatment with a taxane (such as docetaxel), has apparently taken place in both the EU and US.  For men with the disease in the US, approval of this agent could come within six months or even less, but the EMA will likely take a little longer, as they do not have an official priority review process.

It’s mixed blessings for me – too late to help my Dad or my friends Fathers, but hopefully it will represent good news and a new option for other men in their situation who have advanced disease and are too frail for chemotherapy.

You can read more about the data from ESMO here.

{Hat Tip to my buddy @adamfeuerstein of The Street for alerting me promptly to the news}

Nuclear Receptor expression defines a set of prognostic biomarkers for lung cancer

By on December 20, 2010

I’m on a lung cancer and systems biology roll at the moment, although partly that’s just how the interesting data rolls in the literature.

Here’s some new food for thought.  A group of respectable scientists published some fascinating data in PLOS Medicine (free article see reference below) entitled, “Nuclear Receptor Expression Defines a Set of Prognostic Biomarkers for Lung Cancer.”

Using PCR, they evaluated NR expression patterns associated with good and poor outcomes in patients with non-small cell lung cancer (NSCLC) and then validated the findings in lung adenocarcinomas (n=550) and squamous cell carcinoma (n=130) samples in three different analyses by comparing normal and lung cancer cells.  Two important factors emerged from the analysis:

“The prognostic signature in tumors could be distilled to expression of two nuclear receptors, short heterodimer partner (SHP) and progesterone receptor, as single gene predictors of NSCLC patient survival time, including for patients with stage I disease.”

The SHP protein was the better predictor of outcomes in patients with stage I disease; those with strong SHP expression had better overall survival rates of approx. 70% at 100 months compared with 45% among people with low SHP expression.  The survival curves in the paper were quite dramatic – check them out.  Interestingly, the same signatures were also predictive of recurrence based on normal tissue samples from the patients with NSCLC.  Progesterone receptor expression was, however, a much weaker predictor of any outcome based on this analysis.

Essentially, this means the study demonstrated:

“NR expression is strongly associated with clinical outcomes for patients with lung cancer, and this expression profile provides a unique prognostic signature for lung cancer patient survival time, particularly for those with early stage disease.”

What are nuclear receptors, you may be wondering?

“The NR superfamily contains 48 transcription factors (proteins that control the expression of other genes) that respond to several hormones and to diet-derived fats.  NRs control many biological processes and are targets for several successful drugs, including some used to treat cancer.”

Still, it’s not something that immediately springs to mind as a possible or logical prognostic biomarker.

That said, out of the 48 transcription factors, two were found to be related to poorer patient outcomes.  They were NGFIB3, a receptor associated with nerve growth factor, and NR3C2, a mineralocorticoid receptor protein:

“This study highlights the potential use of Nuclear Receptors (NRs) as a rational set of therapeutically tractable genes as theragnostic biomarkers, and specifically identifies short heterodimer partner and progesterone receptor in tumors, and NGFIB3 and MR in non-neoplastic lung epithelium, for future detailed translational study in lung cancer.”

Going forward, we still need to see more research to find out whether these particular NRs or others were involved with tumour development and growth.  If  they do, then NR’s may potentially offer new therapeutic targets for future research and development.

References:

ResearchBlogging.org Jeong, Y., Xie, Y., Xiao, G., Behrens, C., Girard, L., Wistuba, I., Minna, J., & Mangelsdorf, D. (2010). Nuclear Receptor Expression Defines a Set of Prognostic Biomarkers for Lung Cancer PLoS Medicine, 7 (12) DOI: 10.1371/journal.pmed.1000378



FGFR as a target in lung cancer

By on December 17, 2010

Here’s an interesting paper in a new journal I recently signed up for, Science and Translational Medicine.  The journal provides little snapshots of how research can potentially be applied to real life disease.  Here’s a snippet from this particular abstract:

“Lung cancer remains one of the leading causes of cancer-related death in developed countries. Although lung adenocarcinomas with EGFR mutations or EML4-ALK fusions respond to treatment by epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibition, respectively, squamous cell lung cancer currently lacks therapeutically exploitable genetic alterations.

We conducted a systematic search in a set of 232 lung cancer specimens for genetic alterations that were therapeutically amenable and then performed high-resolution gene copy number analyses.

We identified frequent and focal fibroblast growth factor receptor 1 (FGFR1) amplification in squamous cell lung cancer (n = 155), but not in other lung cancer subtypes, and, by fluorescence in situ hybridization, confirmed the presence of FGFR1 amplifications in an independent cohort of squamous cell lung cancer samples (22% of cases).”

Now, squamous cell histology tends to be more associated with smokers than non-smokers and chemotherapy has pretty much been the bedrock of treatment for this group, although it should be noted that in general, currently available therapies either have weak activity or are specifically contraindicated, as in the case of bevacizumab.

Compare this with non-squamous histology, particularly adenocarcinomas, where new molecular targeted therapies have begun to evolve that have extended life and the population tends towards more non-smokers.

Essentially, this is almost like treating two different diseases based on the underlying biology, but this is the first time I’ve seen a potential molecular target reported to be associated with squamous cell histology.

The researchers expanded on their finding that FGFR1 may be a useful target in squamous cell lung cancer by taking an FGFR inhibitor (PD173074) and testing it in an appropriate lung cancer model to see what happened:

“The compound inhibited growth and induced apoptosis specifically in those lung cancer cells carrying amplified FGFR1.”

Next, they looked at an in vivo model with the same FGFR inhibitor and found that it induced tumour shrinkage, which is very promising.

Meanwhile, I did a search in the literature and found a research paper from Pardo et al., who looked at the effects of the same FGFR inhibitor in small-cell lung cancer (SCLC), which accounts for approx. 15% of lung cancers, and is more commonly associated with smoking than non-smoking.  In this disease, many patients are chemo-sensitive, but tend to relapse as resistance sets in.  Pardo’s group found that the FGFRi potentiated the effects of cisplatin, the most commonly used chemotherapy in SCLC.

They also found something else of note:

“More dramatically, in H-69 xenografts, PD173074 induced complete responses lasting >6 months in 50% of mice. These effects were not a consequence of disrupted tumor vasculature but instead correlated with increased apoptosis (caspase 3 and cytokeratin 18 cleavage) in excised tumors.”

Overall, it will be interesting to see what happens with FGFR inhibitors in the clinic going forward.  There are a number in development already, including the following:

  • TKI258 (dovitinib), Novartis
  • AP24534 (ponatinib)
  • AZD4547 (AstraZeneca)
  • FP-1039 (Five Prime)
  • XL999 (Exelixis/GSK) – may have been discontinued

Of note, some of these agents are multi-kinase inhibitors and target other kinases as well, some inhibit FGFR 1 or 2 or 3 and some inhibit FGFR1, 2 and 3, so it will be interesting to see how these shake out.  Advanced solid tumours, leukemia and breast cancer appear to be a common target, but few, if any are considering lung cancer (either squamous NSCLC or SCLC) as a possibility as far as I can see.

ResearchBlogging.org Weiss, J., Sos, M., Seidel, D., Peifer, M., Zander, T., Heuckmann, J., Ullrich, R., Menon, R., Maier, S., Soltermann, A., Moch, H., Wagener, P., Fischer, F., Heynck, S., Koker, M., Schottle, J., Leenders, F., Gabler, F., Dabow, I., Querings, S., Heukamp, L., Balke-Want, H., Ansen, S., Rauh, D., Baessmann, I., Altmuller, J., Wainer, Z., Conron, M., Wright, G., Russell, P., Solomon, B., Brambilla, E., Brambilla, C., Lorimier, P., Sollberg, S., Brustugun, O., Engel-Riedel, W., Ludwig, C., Petersen, I., Sanger, J., Clement, J., Groen, H., Timens, W., Sietsma, H., Thunnissen, E., Smit, E., Heideman, D., Cappuzzo, F., Ligorio, C., Damiani, S., Hallek, M., Beroukhim, R., Pao, W., Klebl, B., Baumann, M., Buettner, R., Ernestus, K., Stoelben, E., Wolf, J., Nurnberg, P., Perner, S., & Thomas, R. (2010). Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer Science Translational Medicine, 2 (62), 62-62 DOI: 10.1126/scitranslmed.3001451

Pardo, O., Latigo, J., Jeffery, R., Nye, E., Poulsom, R., Spencer-Dene, B., Lemoine, N., Stamp, G., Aboagye, E., & Seckl, M. (2009). The Fibroblast Growth Factor Receptor Inhibitor PD173074 Blocks Small Cell Lung Cancer Growth In vitro and In vivo Cancer Research, 69 (22), 8645-8651 DOI: 10.1158/0008-5472.CAN-09-1576

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FDA moves to withdraw Avastin in breast cancer

By on December 16, 2010

Well, the long awaited decision by the FDA on bevacizumab (Avastin) in breast cancer has finally been published and is probably the least surprising decision by the agency in 2010:

“The Office of New Drugs (OND) recommends withdrawing approval of the breast cancer indication for bevacizumab (Avastin).  This indication was approved on February 22, 2008, under accelerated approval provisions for use in combination with paclitaxel for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer.

As a condition of the accelerated approval, Genentech was required to submit data from two ongoing trials (AVADO and RIBBON1) to provide verification of the treatment effect on progression free survival (PFS) and to provide additional information on the effects on overall survival (OS).  These two trials failed to confirm the magnitude of benefit originally observed in the E2100 study on which accelerated approval was based.  In addition, there was an overall increase in serious adverse events related to bevacizumab.

The modest benefit observed with Avastin together with the substantial adverse reactions observed in breast cancer trials to date fail to provide a favorable risk-benefit profile to support continued marketing of Avastin for a first-line metastatic breast cancer indication.  It is the conclusion of OND that the breast cancer indication for Avastin be withdrawn.”

Source: FDA

This is not a surprising decision following the recent ODAC vote of 12-1 to withdraw the drug for the treatment of breast cancer based on the AVADO and RIBBON1 trial results, which was discussed in detail previously on this blog.  The overall survival data actually showed a slight benefit in favour of the chemotherapy (docetaxel) only arm in AVADO, for example, (31.9 vs. 30.2 months).

Also of interest to many is the more results from the neoadjuvant trial with bevacizumab prior to surgery.   Negative trial results were announced at the San Antonio Breast Cancer Symposium last week, essentially adding another nail in the coffin for a solid rationale for earlier use in breast cancer.

For now, the drug will remain on the market and available in this indication, but the clear intent by the FDA is that they plan on withdrawal following the lack of confirmation for full approval.  The company, Roche/Genentech, have 15 days to request a hearing and judging by the press releases so far, this will be sought.  No doubt significant patient advocacy will also be mobilised in support.

There is no question that some women with breast cancer have benefitted from treatment with bevacizumab, but without a biomarker to determine who is most likely to respond to the therapy, it is difficult to see how it can remain on the market given three overwhelming negative trials demonstrating little overall benefit and some not insignificant risk of systemic side effects.

For me, though, what this body of data consistently shows is that, combined with the negative bevacizumab in adjuvant colorectal cancer, VEGF plays a much clearer role in metastatic disease such as colorectal cancer where the tumours are more vascular and often larger.  In breast cancer, the tumours are typically much smaller by comparison.  It may well be that we learn more about the process of angiogenesis from negative data and how tumours grow.  Angiogenesis is a highly complex process and we still need to learn how other growth factors such as PDGF, angiopoeitins, Tie-2 etc, may play a role in tumour growth.  This has yet to be elucidated but research is ongoing.  The recent post discussing cancer cell seeding teaches us that we have much to learn about the whole process of angiogenesis from early growth to metastasis.  VEGF is clearly not the only target involved.

Meanwhile, this developing story will clearly continue to unfold in 2011.  The New York Times has a different angle on this story, so check it out for yourselves.

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DNA-Repair Pathways: Cancer Syndromes to Novel Therapies

By on December 15, 2010

Today I’m delighted to announce that we have a guest post from Adam Bristol, Ph.D, who works for Aquilo Capital Management in San Francisco.  Adam helps to manage a life sciences investment fund, where they invest in new drug discovery and drug development companies.  He also told me that his scientific training was in neuroscience, but “I’ve become absolutely fascinated with oncology and virology since I left the lab.” This is wonderful to hear and his enthusiasm really comes across in his report below.

At the recent American Society of Hematology meeting I was a tad grumpy at not being able to attend one of the science sessions and a lively discussion followed in the comments.  Adam wrote that he was attending the session and kindly offered to share his notes with the PSB community, which I’m delighted to post forthwith…

Readers of the PharmaStrategy Blog will be familiar with a scientific session entitled, “DNA-Repair Pathways: Cancer Syndromes to Novel Therapies” held on Monday afternoon at the recent ASH meeting.  With an expanding list of PARP inhibitors advancing in the clinic for multiple tumor types, and a growing literature on the biology of DNA repair mechanisms, this session promised to be a terrific overview of an emerging treatment paradigm.  However, as noted in an earlier post here, the conference program stated that attendance was limited to “medical professionals” only, thereby excluding a significant portion of ASH attendees.  While I’m not a medical professional, I was permitted to attend the session, perhaps because I registered before the restriction was imposed.  Below is the published abstract for the session and my take-aways from a very engaging presentation and discussion, which was chaired by Drs. Alan D’Andrea (Dan-Farber Cancer Institute) and Michael Kastan (St. Jude Children’s Research Hospital).  As with all scribbled notes on oral presentations, mine required some decoding as I began my write-up.  Corrections and elaborations from readers are more than welcome!

Here is a quick synopsis of the session from ASH:

“Conventional anticancer therapy (chemotherapy and radiation) kills tumor cells by causing DNA damage. Tumors differ in their response to these agents, at least in part, through their variable levels of DNA-repair activity. Human tumor cells have six independent DNA-repair pathways, including base-excision repair (BER), nucleotide-excision repair (NER), homologous recombination (HR), mismatch repair (MMR), non-homologous endjoining (NHEJ), and translesion DNA synthesis (TLS). Here, we will discuss the six major DNA-repair pathways found in human tumors, the relevant inherited cancer syndromes, the available biomarkers for assessing these pathways, and the emerging class of drugs referred to as DNA-repair inhibitors. These inhibitors, including those that target PARP or the ATM protein kinase, block DNA-repair pathways and can enhance the sensitivity of tumor cells to conventional therapy. Dr. Alan D’Andrea will discuss the Fanconi anemia/BRCA pathway and its synthetic lethal relationship with other DNA-repair mechanisms. Pharmacologic modulation of this pathway has led to novel therapies for cancer and for bone marrow failure. Dr. Michael Kastan will review another critical DNA-damage-response pathway, the ATM-p53 pathway. This pathway presents opportunities for development of novel anticancer agents, including potential approaches for both radiosensitization and radiation- or chemo-protection. As with the Fanconi anemia/BRCA pathway, the concept of synthetic lethality may also apply to this signaling pathway. Thus, targeting these pathways could lead to preferential killing of tumor cells based on the genetic or microenvironmental abnormalities in the tumors.”

Dr. D’Andrea’s presentation led off the session. He first noted that cancer cells are often defective in a DNA repair pathway and that this deficiency alters sensitivity to DNA-damaging chemotherapeutic agents. This leads to the possibility that knowing the status of DNA repair pathways could aid in predicting tumor sensitivity to chemotherapy. He cited a few examples, such as loss of BRCA1 and sensitivie to PARP inhibitors, low levels of DNA excision repair protein ERCC-1 predictive of cisplatin sensitivity, and levels of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) associated with temozolomide sensitivity/resistance.

D’Andrea then summarized a significant amount of work that he and his colleagues have conducted on Fanconi Anemia (FA), a rare disease resulting from defects in thirteen DNA repair proteins, specifically the DNA repair response to cross-linking agents. Consequently, FA patients are hypersensitive to mitomycin C (MMC) and other cross-linking agents.  Three of the thirteen FA genes, including BRCA2, are known to be susceptibility genes for breast cancer and ovarian cancer.  D’Andrea proposed that loss of ubiquitination of the D2 Fanconi protein (FANCD2) can be useful biomarker of tumor susceptibility to DNA damaging agents because this ubiquitination step is the results of a DNA-damage-induced assembling of eight FA proteins into a multi-protein complex that acts as a E3 ubiquitin ligase that mediates the repair process.  In other words, because knocking out any of the protein in this process causes FA, tumors with low or no ubiquitination of FANCD2 should be sensitive to MMC or cisplatin.  He cited data showing that 20% of ovarian cancer biopsies showed deficits in the FA pathway (likely due to silencing by epigenetic events, such as methylation).

Ovarian cancer was not the only tumor type with a deficient FA pathway:

  • 18% of breast cancers
  • 15% of NSCLC
  • 15% squamous cell head and neck cancers
  • 35% cervical cancers

Sporadic AML, including those with the complex karyotypes of secondary AML, also commonly harbor FA deficiencies.  Dr. D’Andrea noted that de-methylatation, and thus restoration of FA pathway DNA repair, can also occur, and that this could be mechanism of tumor resistance.  Thus, serial tracking of FANCD2 ubiquitination can be used to track resistance.

He next raised the question of whether the FA pathway is druggable to effectively sensitize tumors to chemo agents.  That is, can we inhibit the mono-ubiquitination of FANCD2?  D’Andrea briefly reviewed the results of a chemical screen that found three kinase inhibitors but, importantly, also bortezomib (Velcade), inhibited FANCD2 ubiquitination.  Subsequent in vitro data showed that bortezomib sensitized ovarian cancer cell lines to cisplatin, both when bortezomib was administered as a pre-treatment or when administered concurrently with cisplatin.  Based on these and other data, they are currently running a Phase 1b trial of bortezomib in combination with cisplatin.

Lastly, Dr. D’Andrea discussed the concept of synthetic lethality and PARP inhibitors. Inhibitors of PARP, which stands for poly (ADP-ribose) polymerase, work because, in breast cancer tumors, cells become reliant on a specific DNA repair pathway, specifically base-excision repair.  He called them “essentially homologous-repair deficient tumors”, meaning that breast cancer tumor have lost that DNA repair pathway.  The problem, he said, is that resistance to PARP inhibitors has already been observed and that secondary tumors can be error-free in their repair.  At present, the rules for tumor specificity/sensitivity to PARP inhibitors is not well understood.  The question of resistance to PARP inhibitors resurfaced in the Q&A, at which time Dr. D’Andrea explained that the mechanism is not completely known but that it may be due to somatic reversion, i.e., mutant allele reverting to WT-like allele, thus reinstating the HR repair pathway.

Dr. Kastan gave the second talk of the session, beginning his remarks with a particularly sobering reminder: DNA is damaged in many ways, for example:

  • on purpose, such as when we are intentionally exposed to X-rays
  • on accident, such as when we are subjected to excessive sun exposure
  • unavoidably, such as the damage due to production of reactive oxygen species, a natural byproduct of cellular metabolism and ageing.

He cited the incredible estimate that our cells deal with ~10,000 instances of DNA damage per cell per day!  Exploration of DNA repair pathways is therefore relevant to the areas of metabolism, apoptosis and autophagy, noting specifically that interest in autophagy is really exploding at present.  Autophagy is a process of cellular self-destruction in which organelles and macromolecules are targeted and degraded by the lysosome.  In general, apoptosis and autophagy are important brakes on tumorigenesis and deficiencies in these processes, such as by alteration in tumor suppressor genes, are common proliferative strategies.

He noted that Arf/p53 tumor suppressor pathway is responsive to DNA damage (among other signals), in part through activation by Ataxia-Telangiectasia-mutated (ATM) protein kinase.  For example, ionizing irradiation activates ATM as does chemotherapy. Similarly, mutations in ATM (as in ataxia-telangiectasia, the kinase’s namesake) and a related kinase, ATM- and Rad3-related (ATR) kinase, have been shown to render mice and humans hypersensitive to ionizing radiation.  Thus, in theory, an ATM inhibitor could be a chemosensitizer.  It turns out that caffeine is an ATM/ATR inhibitor, but with poor potency.

Dr. Kastan and his colleagues have collaborated with Pfizer scientists to identify novel small molecule ATM inhibitors.   They’ve published on first generation compounds, and are now onto next generation molecules, specifically to explore the SAR, increase bioavailability, and perform siRNA screens for other related targets.  Achieving ATM/ATR selectivity would be challenging, however, as the enzymes are closely related.

On the other hand, activation of ATM kinase and subsequent induction of Arf/p53 could serve as a tumor prevention strategy.  Chloroquine, a anti-malarial drug originally discovered in the 1930’s, activates the ATM kinase and induces Arf/p53 without damaging DNA.  In a mouse model of ATM-deficient, Myc-driven tumors (a model of Burkitt lymphoma), Kastan showed (in Maclean et al., JCI, 2008) that weekly, low dose choloquine could prevent spontaneous de novo lymphomas.  He also cited clinical epidemiological data in which incidence of lymphoma in Tanzania was reduced by 75% during a trial of chlorquine as a treatment for malaria (the investigators were testing the hypothesis that malaria was a causative factor in development of Burkitt lymphoma, thus the collection of the incidence data).  Strikingly, the incidence rate returned to the pre-trial baseline within two years of the study’s completion.

Dr. Kastan also noted that a paper in Science in 1999 described pifithrin-alpha has capable of inhibiting p53 activation and preventing chemotherapy-induced apoptosis (a potential strategy to prevent an unwanted side effect in normal tissues), but the exact mechanism is still unclear.   He also discussed the use of phosphorylated ATM is a potential biomarker of ROS status.

In my opinion, both speakers presented compelling case studies of bench-to-bedside translational science; in each case, an understanding of the cell signaling pathways, their alteration and involvement in tumorigenesis and progression yielded therapeutic targets and novel treatment strategies.  I hope we see additional advances as this field progresses.

References:

ResearchBlogging.org Komarov PG, Komarova EA, Kondratov RV, Christov-Tselkov K, Coon JS, Chernov MV, & Gudkov AV (1999). A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science (New York, N.Y.), 285 (5434), 1733-7 PMID: 10481009

Maclean, K., Dorsey, F., Cleveland, J., & Kastan, M. (2008). Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis Journal of Clinical Investigation, 118 (1), 79-88 DOI: 10.1172/JCI33700

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