Epigenetics – an emerging new potential treatment for lung cancer?

By MaverickNY on November 11, 2011

A couple of articles in the latest Cancer Discovery looked at some rather promising, and perhaps a little unexpected, findings pertaining to epigenetic therapy.

What are epigenetics?

If you read up on epigenetics in the medical journals, you will come across some of the most dense and complex articles I’ve ever come across in cancer biology. That said, there are a few readable examples around such as Bird’s (2007) short insight piece in Nature.

Personally, I tend to think of epigenetics – in very simple terms – as changes in gene function that can occur without a change in the sequence of the DNA. This means that we see things such as DNA methylation (where something new is added) and gene silencing (where something important is somehow switched off or lost). A classic change in cancer that often appears in many tumour types is PTEN loss, for example.

As Rodriquez-Paredes and Esteller (2011) noted in their editorial,

“No one doubts that tumorigenesis is a consequence of not only genetic but also epigenetic alterations…

Cancer epigenomes are characterized by global changes in DNA methylation and covalent histone modification patterns.”

What types of epigenetic therapy are there?

While some readers might be vaguely familiar with DNA methylating agents and histone deacetylase inhibitors (HDAC), there are quite a few other types in preclinical development including:

histone methyltransferase inhibitors
histone kinase inhibitors
sirtuin inhibitors
microRNA-related compounds

and others, to name a few.

Currently, however, there are a couple of epigenetic therapies that have been approved (eg SAHA or vorinostat), which belongs to the histone deactelyase class of inhibitors (HDAC) indicated for CTCL, while another is the DNA methyltransferase inhibitors (eg azacitadine/Vidaza and decitabine/Dacogen), which are approved for the treatment of MDS and AML, respectively. There are also several other HDACi in development, including entinostat (Syndax), which has shown activity in breast and lung cancers (see Huang et al., 2009 as an example) and panobinostat (Novartis), which is being evaluated in both hematologic malignancies and solid tumours (prostate and melanoma).

Yet what really caught my attention in the paper by Jeurgens et al., (2011) and the accompanying editorial (see references below) was that these two therapy classes are being evaluated in combination for… lung cancer. You likely won’t find HDACs or DNA methyltransferase inhbitors in the top 30 of therapies used for lung cancer at present, but that may change sooner than you think.

Background to epigenetics in lung cancer

To put this story in context, the authors (see Brock et al., 2008) previously identified a potential gene signature for recurrence associated with stage I lung cancer after surgical resection:

“Analysis of DNA methylation in tumors and mediastinal lymph nodes from a series of patients with surgically resected stage I NSCLC defined several prognostic markers associated with rapid tumor recurrence.

Four gene targets of tumor-specific epigenetic silencing, CDKN2a, CDH13, APC, and RASSF1a, were identified as strongly associated with disease recurrence and death, both singly and in combination.

Methylation of any 2 of these 4 target genes in tumor and mediastinal lymph nodes conferred a markedly worse prognosis in patients with stage I lung cancer (P < 0.001), similar to patients with stage III disease.”

As far as I’m aware, to date the clinical data with epigenetic therapies has been reported in hematologic malignancies such as leukemia, lymphoma and MDS. This is the first time we’ve seen some meaningful data in solid tumours.

What about the latest clinical trial in lung cancer?

Jeurgens and colleagues at Johns Hopkins conducted:

“A phase I/II trial of combined epigenetic therapy with azacitidine and entinostat, inhibitors of DNA methylation and histone deacetylation, respectively, in extensively pretreated patients with recurrent metastatic non–small cell lung cancer.
This therapy is well tolerated, and objective responses were observed, including a complete response and a partial response in a patient who remains alive and without disease progression approximately 2 years after completing protocol therapy.”

The NSCLC patients (n=45) were mainly smokers or former smokers (n=40) with primarily adenocarcinoma (n=34) who had been heavily pre-treated (median of 3 prior therapies).

Median overall survival in the entire group was 6.4 months, which compared favourably with the expected 4.0 months in historical controls.

“Four of 19 patients had major objective responses to subsequent anticancer therapies given immediately after epigenetic therapy.”

These responses in a small subset of patients were fascinating – the most dramatic response was seen in one patient who experienced a complete response (CR) that lasted for 14 months. A further 10 people had stabilisation that lasted at least 12 weeks (1 for 14 months and another for 18 months).

Moreover, the four gene signature referred to earlier turned out to be potentially useful as both a prognostic and predictive biomarker:

“Demethylation of a set of 4 epigenetically silenced genes known to be associated with lung cancer was detectable in serial blood samples in these patients and was associated with improved progression-free (P = 0.034) and overall survival (P = 0.035).”

One patient who did particularly well on the combination therapy was subsequently re-challenged with chemotherapy and had such a good response that the nodules in his lungs reduced significantly. After being diagnosed in December 2006 with stage IV NSCLC, he was still alive and well to tell his astonishing and heartwarming story on the press conference five years later.

Overall, the authors rightly concluded that:

“This study demonstrates that combined epigenetic therapy with low-dose azacitidine and entinostat results in objective, durable responses in patients with solid tumors and defines a blood-based biomarker that correlates with clinical benefit.”

Emphasis mine.

While these results are very exciting, they are also preliminary and will need to be validated in larger scale clinical trials along with the blood biomarkers for clinical response. They do offer a very strong proof of concept for the combination of epigenetic therapy with a DNA methyltransferase inhibitor and an HDAC inhibitor with clear activity in a subset of patients.

What do these results mean in practice?

Personally, I thought these results were absolutely fascinating and offer us a glimpse into the future where we can utilise epigenetic therapies to:

Effectively repair damaged DNA in tumours
Offer low dose therapies with fewer side effects that give a respite from chemotherapy, while doing more good than harm
Enable sensitization of subsequent therapies to improve outcomes
Predict which patients are most likely to respond to epigenetic therapies, while sparing those unlikely to from any systemic side effects

To get a good clinical perspective of what these results mean, I spoke with Dr Jeff Engelman, Director, Center for Thoracic Cancers at Mass General in Boston. He described the data as ‘impressive’:

“I don’t think this is going to impact the practicing oncologist today, but from a scientific stand point, from an oncology development stand point, from a future stand point, it is I think impressive to many of us, to me.

Seeing that epigenetics could have a dramatic effect even on a subset of lung cancers, we’ve never seen epigenetic modulators have such an effect on solid tumors, so it really opens the door that this may be another type of therapy that we will be able to employ for the right patients. A totally different type of approach.”

He also went on to put the story in a broader context, which I thought was very helpful:

“It is somewhat analogous to the first trials with EGFR inhibitors where had we treated 40 patients with those we would have seen a few great responses.”

“With EGFR, it was given to tons of patients, and there was a subset that responded, and it took a couple of years to find out why. Then all of sudden, boom everything makes sense and we go forward. This feels more like that, we have seen some great responses and now need to figure out why.”

Clearly, the gene signature identified by Brock et al., (2008) in stage I patients needs to be validated in a broader population of patients in clinical trials, but at least it offers a starting point to try and determine which patients with lung cancer might respond to epigenetic therapy. I think Engelman is correct here; once we determine the right biomarkers of response and how often they occur, then patients with lung cancer can be screened and appropriate therapy offered, whether that be EGFR therapy, ALK therapy, or something completely different such as treatment with epigenetic drugs.

The amazing thing is how much progress is being made of late in lung cancer and that’s very good news indeed. I look forward to hearing more about this story and also the other slices or targets as they are identified and the story evolves further.

References:

Bird, A. (2007). Perceptions of epigenetics Nature, 447 (7143), 396-398 DOI: 10.1038/nature05913

Brock, M., Hooker, C., Ota-Machida, E., Han, Y., Guo, M., Ames, S., Glöckner, S., Piantadosi, S., Gabrielson, E., Pridham, G., Pelosky, K., Belinsky, S., Yang, S., Baylin, S., & Herman, J. (2008). DNA Methylation Markers and Early Recurrence in Stage I Lung Cancer New England Journal of Medicine, 358 (11), 1118-1128 DOI: 10.1056/NEJMoa0706550

Huang, X., Gao, L., Wang, S., Lee, C., Ordentlich, P., & Liu, B. (2009). HDAC Inhibitor SNDX-275 Induces Apoptosis in erbB2-Overexpressing Breast Cancer Cells via Down-regulation of erbB3 Expression Cancer Research, 69 (21), 8403-8411 DOI: 10.1158/0008-5472.CAN-09-2146

Juergens, R., Wrangle, J., Vendetti, F., Murphy, S., Zhao, M., Coleman, B., Sebree, R., Rodgers, K., Hooker, C., Franco, N., Lee, B., Tsai, S., Delgado, I., Rudek, M., Belinsky, S., Herman, J., Baylin, S., Brock, M., & Rudin, C. (2011). Combination Epigenetic Therapy Has Efficacy in Patients with Refractory Advanced Non-Small Cell Lung Cancer Cancer Discovery DOI: 10.1158/2159-8290.CD-11-0214

Rodriguez-Paredes, M., & Esteller, M. (2011). A Combined Epigenetic Therapy Equals the Efficacy of Conventional Chemotherapy in Refractory Advanced Non-Small Cell Lung Cancer Cancer Discovery DOI: 10.1158/2159-8290.CD-11-0271

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Update on pancreatic Neuroendocrine Tumours (NET)

By MaverickNY on November 10, 2011

Today on 10th November, it’s the Second Annual Worldwide NET (Neuroendocrine Tumor) Cancer Awareness Day. Granted that’s a bit of a mouthful, but it also seems poignant given so many of my news feeds this morning were still full of Steve Jobs, who sadly passed away from the disease last month.

I’ve been meaning to post an update on this rare form of cancer all year, given that we now have targeted therapies now approved by the FDA for treatment, but things were hectic at the office and then with Jobs passing, the timing just seemed tacky and inappropriate.

The idea though, of an Awareness Day for a rare disease such as NET to improve both education and awareness seems an inherently good one to me, especially as there has been some progress clinically in 2011. According to Kulke et al., (2011) NET has an incidence of around 1 per 100,000 individuals. This excellent review covers the key essentials of both the disease and the treatments:

“Patients with pancreatic NET present with diverse symp- toms related to hormonal hypersecretion, tumor bulk, or both. Accurate diagnosis of this condition and differentiation of pancreatic NET from the more common pancreatic adenocarcinomas is a critical first step in developing an appropriate treatment plan.”

It has been quite the landmark year for NET since not one, but two, new therapies were approved by the FDA in May this year with very different mechanisms of action:

Everolimus (Afinitor) from Novartis targets the mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway.
Sunitinib (Sutent) from Pfizer is a multikinase inhibitor of VEGF, PDGFR (α and β), KIT, FLT3, RET and CSF-1R.

Both of these drugs are also approved for the treatment of renal cell cancer, which while nearby geographically in the body, is a completely different type of GI cancer. They are now approved for pancreatic neuroendocrine tumours (pNET) that have progressed and cannot be treated with surgery.

It is important to note, that while NET is a rare form of pancreatic cancer, it is not the same thing as the more common pancreatic adenocarcinoma – a fact that the media often got wrong in the case of Steve Jobs and drove me potty at their ignorance and inability to grasp a simple concept. NET is not an adenocarcinoma and has a much larger endocrinology/metabolism component and starts in the hormone-producing cells of the pancreas. There are two types of pancreatic NET:

Functional (overproduce hormones)
Nonfunctional (do not overproduce hormones) and are more common

There are some great resources for patients (and caregivers) want to know more about this disease – here are some examples I came across:

The Pancreatic NET Connections site sponsored by Pfizer gives some great education about the disease
The NET Alliance site is sponsored by Novartis and offers lots of useful information
Pancreatic Cancer Action Network has a nifty Facebook page
The American Cancer Society has information about treatments

Let’s take a look at the new clinical data. Both sunitinib and everolimus were compared to placebo in the phase III trial of refractory patients who were ineligible for surgery and had disease progression.

Here’s what the survival curves look like, based on the data from their respective prescribing information: 1 2

In the case of sunitinib, we can see that the median progression-free survival (PFS) 10.2 months versus 5.4 months for the placebo arm. This difference was highly significant (P 0.000146, HR 0.427):

sunitinib

Looking at the everolimus data, we also see a significant trend in favour of therapy over placebo, i.e. a median PFS of 11.04 months compared with 4.6 months for placebo (P 0.001, HR 0.35):

everolimus

These studies produced very comparable responses from a survival perspective and overall response rates of 9% and 5%, respectively.

While it is good to see some excellent progress on the efficacy front, these new therapies for NET are not without their challenges and side effects though.

In particular, in the phase III study, sunitinib, hypertension was the most common grade 3 event in 10% of patients (a classic function of the VEGF class of drugs) and was also shown to cause cardiac failure leading to death in 2/83 (2%) patients on therapy compared with no patients on placebo.

In contrast, everolimus should be avoided with concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole). The most common grade 3/4 adverse reactions (incidence ≥ 5%) in the phase III pNET trial were stomatitis and diarrhea.

As Kulke et al., observed:

“Surgical resection remains the mainstay of treatment for patients with localized disease.”

However, for patients who are unresectable or have progressed there are at last new options:

“Recent studies have also reported that the tyrosine kinase inhibitor sunitinib and the mTOR inhibitor everolimus improved progression-free survival in patients with pancreatic NET, further expanding the therapeutic arsenal available to patients with this disease.”

In the future, we may well see sequencing studies emerge as well as other targeted therapies to prolong outcomes for patients with this rare disease.

References:

Kulke MH, Bendell J, Kvols L, Picus J, Pommier R, & Yao J (2011). Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumors. Journal of hematology & oncology, 4 PMID: 21672194

Sunitinib PI accessed ↩
Everolimus PI accessed ↩

Redefining subsets of triple negative breast cancer

By MaverickNY on November 9, 2011

Heterogeneity remains one of the biggest barriers to progress in clinical research. Triple negative breast cancer is an excellent example of this conundrum as I’ve said many times here on this blog – it’s defined not what it is but what it’s not. By that, I mean it’s a broad catch-all for all those women with breast cancer who are essentially ER/PR- HER2- but beyond that are likely other subsets yet to be identified or characterised.

That said, once we have a better sense of what those smaller groups are (from basic and translational research) then progress with targeted therapeutics is much more likely. Why? Because by reducing the inherent variability we increase the chances of success with a given target. If you don’t have a valid and well defined target to aim at then the risks of a negative result in large scale clinical trials are much much higher.

We may also see a new subgroup breast cancers emerge defined solely by their ER/PR- status irrespective of the HER gene. This in itself would be an interesting idea as it lends itself well to the current grouping of patients.

Nature Genetics

This morning’s coffee browsing in Nature Genetics brought up something that piqued my interest greatly – Haiman and colleagues sent in a Letter reporting on a common risk variant for ER- breast cancer associated with chromosome 5P5, i.e. the TERT-CLPTM1L locus.

The essence of their research was given ER- breast cancer tends to be higher in women of African than European ancestry and confers a poorer prognosis, what common risk alleles could be identified? They collated information from genome-wide association study (GWAS) data in women of African (n=1,004 ER-, n=2,745 controls) and European (n=1,718 ER-, n=3,670 controls) ancestry. Here’s what they found:

“The (5P5) variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer, particularly in younger women (defined as less than 50 years of age).”

In addition, they also observed that:

“In combining the results across all studies (6,009 ER-negative cases and 20,708 controls with genotype data), rs10069690 was significantly associated with an increased risk of ER-negative breast cancer.”

What particularly struck me, however, was a little nugget buried deep in the discussion:

“We found no significant association with rs1006960 among ER- and PR-positive cases when stratified by HER2 status.”

In other words, it is the estrogen receptor status that is the defining characteristic. This suggests that not all triple negative women will behave in the same way, so identifying the factors that are important may change our thinking in how to approach patients in the future.

What do these findings mean?

This study is important because it identifies, for the first time, an aberration ie a common variant at the TERT-CLPTM1L locus that is associated with ER- breast cancer that also tended to occur in younger women. As we begin to dig deeper into the molecular biology of ‘triple negative breast cancer’, I use parentheses loosely here as that definition may one day change with more research, we are likely to:

Define new subsets of patients who may respond differently
Identify possible new targets for clinical trials of rationally targeted agents
Smaller trials will be needed for well-defined subsets that have a greater chance of a good response, this in turn makes an accelerated development potentially possible as we saw recently with crizotinib for ALK-positive lung cancer.

I look forward to following the burgeoning research in this area and suspect that we will see many more groups begin to isolate and identify important aberrations that drive the disease and offer new targets for therapeutic intervention.

References:

Haiman, C., Chen, G., Vachon, C., Canzian, F., Dunning, A., Millikan, R., Wang, X., Ademuyiwa, F., Ahmed, S., Ambrosone, C., Baglietto, L., Balleine, R., Bandera, E., Beckmann, M., Berg, C., Bernstein, L., Blomqvist, C., Blot, W., Brauch, H., Buring, J., Carey, L., Carpenter, J., Chang-Claude, J., Chanock, S., Chasman, D., Clarke, C., Cox, A., Cross, S., Deming, S., Diasio, R., Dimopoulos, A., Driver, W., Dünnebier, T., Durcan, L., Eccles, D., Edlund, C., Ekici, A., Fasching, P., Feigelson, H., Flesch-Janys, D., Fostira, F., Försti, A., Fountzilas, G., Gerty, S., Giles, G., Godwin, A., Goodfellow, P., Graham, N., Greco, D., Hamann, U., Hankinson, S., Hartmann, A., Hein, R., Heinz, J., Holbrook, A., Hoover, R., Hu, J., Hunter, D., Ingles, S., Irwanto, A., Ivanovich, J., John, E., Johnson, N., Jukkola-Vuorinen, A., Kaaks, R., Ko, Y., Kolonel, L., Konstantopoulou, I., Kosma, V., Kulkarni, S., Lambrechts, D., Lee, A., Marchand, L., Lesnick, T., Liu, J., Lindstrom, S., Mannermaa, A., Margolin, S., Martin, N., Miron, P., Montgomery, G., Nevanlinna, H., Nickels, S., Nyante, S., Olswold, C., Palmer, J., Pathak, H., Pectasides, D., Perou, C., Peto, J., Pharoah, P., Pooler, L., Press, M., Pylkäs, K., Rebbeck, T., Rodriguez-Gil, J., Rosenberg, L., Ross, E., Rüdiger, T., Silva, I., Sawyer, E., Schmidt, M., Schulz-Wendtland, R., Schumacher, F., Severi, G., Sheng, X., Signorello, L., Sinn, H., Stevens, K., Southey, M., Tapper, W., Tomlinson, I., Hogervorst, F., Wauters, E., Weaver, J., Wildiers, H., Winqvist, R., Berg, D., Wan, P., Xia, L., Yannoukakos, D., Zheng, W., Ziegler, R., Siddiq, A., Slager, S., Stram, D., Easton, D., Kraft, P., Henderson, B., & Couch, F. (2011). A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor–negative breast cancer Nature Genetics DOI: 10.1038/ng.985

How a metabolic protein PKM2 may have a key role in tumorigenesis

By MaverickNY on November 8, 2011

This morning I was taking a breather from work to catch up on my Science and Nature reading.

Source, Wikipedia: Pyruvate Kinase Muscle isoenzyme

There was a most intriquing Letter to Nature from Lu and colleagues at MD Anderson, describing how PKM2 (pyruvate kinase muscle) may not just have an established role to play in metabolism (via the Warburg effect in glycolysis), but how it may also have important non-metabolic functions in tumour formation and growth:

“Here we demonstrate, in human cancer cells, that epidermal growth factor receptor (EGFR) activation induces translocation of PKM2, but not PKM1, into the nucleus, where K433 of PKM2 binds to c-Src-phosphorylated Y333 of b-catenin.”

In other words, it directly contributes to gene transcription for cancer cell proliferation.

From a scientific point of view, understanding the process of tumorigenesis, ie tumour formation and growth, is critical to figuring out how to stop it. If we know precise elements of the process, then a more targeted and focused approach can be used in the clinic based on a solid rationale that has a better chance of success. That’s much more sensible than literally throwing mud at walls randomly and hoping something sticks!

It is well known that EGFR activation and PKM2 expression are instrumental in tumorigenesis, but the question is how and what:

“These findings reveal that EGF induces b-catenin transactivation via a mechanism distinct from that induced by Wnt/Wingless and highlight the essential non-metabolic functions of PKM2 in EGFR-promoted b-catenin transactivation, cell proliferation and tumorigenesis.”

The researchers also went onto to note that:

“PKM2-dependent b-catenin transactivation is instrumental in EGFR promoted tumour cell proliferation and brain tumour development. In addition, positive correlations have been identified between c-Src activity, b-catenin Y333 phosphorylation and PKM2 nuclear accumulation in human glioblastoma specimens.”

The basis for this idea came from an analysis of samples from tumours of patients with glioblastoma (n=84) who had been previously treated with radiation and chemotherapy after surgery.

They observed that patients who had low beta-catenin Y333 phosphorylation or low expression of PKM2 in the nucleus (n=28 each) had a median survival of 185 weeks and 130 weeks, respectively.

However, median survival decreased for those who had high levels of beta-catenin phosphorylation or nuclear PKM2 expression (n=56 each) to 69.4 weeks and 82.5 weeks, respectively.

Overall, there were a number of important findings, as explained in MD Anderson’s excellent press release describing the work:

“PKM2-dependent beta-catenin activation is instrumental in EGFR-promoted tumor cell proliferation and brain tumor development.

c-Src activity, beta-catenin Y333 phosphorylation, and PKM2 nuclear accumulation are positively correlated in human glioblastoma (GBM) specimens.

Levels of beta-catenin phosphorylation and nuclear PKM2 are correlated with grades of glioma malignancy and prognosis.”

Significance of these results

These results are not only unexpected, they also have some future practical implications, becuase EGFR inhibitors have not proven useful therapeutically in GBM:

New biomarkers: c-Src-dependent beta-catenin Y333 phosphorylation levels could potentially be used as a biomarker for selecting patients for treatment.
New treatment approaches: Src inhibitors (eg dasatinib, bosutinib, saracatinib) in an appropriately selected patient population most likely to respond, as opposed to allcomer trials, where the inherent tumour heterogeneity hides the positive treatment effect of responders.

This is an important article and well worth taking a few minutes out of your day to read.

References:

Yang, W., Xia, Y., Ji, H., Zheng, Y., Liang, J., Huang, W., Gao, X., Aldape, K., & Lu, Z. (2011). Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation Nature DOI: 10.1038/nature10598

Excellent news in Advanced Prostate Cancer – Medivation's MDV3100 meets primary endpoint

By MaverickNY on November 3, 2011

It’s not often that you wake up to really exciting news in the cancer field, but that’s what happened this morning with Medivation’s announcement on the interim analysis of their androgen receptor (AR) antagonist, MDV3100:

“As reported by the IDMC, MDV3100 produced a 4.8-month advantage in median overall survival compared to placebo.

The estimated median survival for men treated with MDV3100 was 18.4 months compared with 13.6 months for men treated with placebo. MDV3100 provided a 37 percent reduction in risk of death compared to placebo (Hazard Ratio=0.631).

The IDMC further determined, considering the observed safety profile, that MDV3100 demonstrated a favorable risk-to-benefit ratio sufficient to stop the study.”

The 4.8 month improvement in OS in post-chemo setting is superior to that previously reported for abiraterone (Zytiga), which had a 3.9 month advantage over placebo and received regulatory approval in the US and EU earlier this year.

This is great news for patients, for Medivation and also for Charles Sawyers at MSKCC who originally invented the MDV3100 compound. If you are interested in the MDV3100 story, you can read my interview with Dr Sawyers posted earlier this year.

There are several points to note about these results:

MDV3100 does not require concomittant steroid therapy as abiraterone does, this is huge for urologists who as surgeons do not generally want to manage side effects.
Given the excellent results in the post chemotherapy setting, I would expect the survival advantage in the pre-chemotherapy session for both therapies to be more than 6 months.
Ultimately, as hormone therapy, I can see the real advantage for MDV3100 being as a more potent and complete inhibitor of the AR than bicalutamide, so there is a huge potential for MDV3100 as ADT therapy in the earlier stages of disease.

With regards to filing, Medivation announced that:

“Medivation and Astellas plan to hold a pre-NDA meeting with the U.S. Food and Drug Administration (FDA) in early 2012 and will provide an update on regulatory timelines for MDV3100 subsequent to that meeting.”

At this rate, I would expect to see MDV3100 approved sometime in 2012.

The future is looking very bright indeed for patients with advanced prostate cancer – these new therapies offer the potential with sequencing to extend lives significantly.

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Understanding cancer metastasis – possible new therapeutic targets

By MaverickNY on November 1, 2011

“Scientists at Dalhousie University in Nova Scotia have identified a key mechanism of metastasis that could lead to blocking tumor growth if their findings are confirmed.”

AACR press release

Loved this opening to an AACR press release about a key paper (freely available for anyone to download – see the reference session below) that was just published in Cancer Research by David Waisman’s group.

Now, before getting into the technical details, I was reflecting recently on both my recent awesome trip to the MD Anderson basic research campus at Smithville, Austin where a lot of research into tumorigenesis is conducted and pointed questions from patients about why their hasn’t been enough progress in treating and curing metastatic breast cancer.

There are several obvious reasons for this:

We need to understand more about the basic mechanisms underpining function, never mind work out what role various proteins have and how they interact in health and disease before we can even think about clinical progress.
As we learn more about the basic process of tumorigenesis, so we can start to apply those findings to clinical research and translational medicine in developing better predictive biomarkers that are clinically meaningful.
If we have excellent biomarkers, an understanding of the processes and the targets involved, thus we should have clearer targets that suggest more logical combinations to treat disease and essentially slow or even undo the process of metastasis.

Quite frankly, based on the little we really know about the underlying biology of advanced disease, I’m sometimes surprised the results are as good as they are. That’s not to say we’re doing great, becasue clearly there is a lot of improvement that can be made, but sometimes we should stop and look at how far we’ve come and ask serious questions about what we really need to know now that can help progress things?

With all that context in mind, the current published research from Phipps et al., (2011) is worth looking at because it advances our thinking a little more. In the past, people have focused on cancer cells, thinking they were the main thing that mattered. What’s interesting about this research is that it shows how important other cells, such as macrophages, are in the tumorigenesis process:

“There is an increasingly large body of evidence correlating tumor-associated macrophage (TAM) density with poor prognosis in a varied number of solid tumors.”

Source: wikipedia

We also know from basic research that macrophages are critical in driving tumour growth, invasion, and metastasis. Macrophages are like the Pacmen of cells – think of them moving around the blood stream chomping things in their wake. The thing is, there are always macrophages in tumours – so how do they get from the bloodstream to the tumour?

The current paper details the key role that the macrophage cell surface protein, S100A10, plays in mediating macrophages, thereby allowing them to move to the site of tumour growth. This process is obviously essential to tumour development and angiogenesis.

What also struck me though, was the research also detailed what happened in animals without the S100A10 protein:

“Growth of murine Lewis lung carcinomas or T241 fibrosarcomas was dramatically reduced in S100A10- deficient mice compared with wild-type mice.

Emphasis mine.

What does all this data mean?

In order to either slow or stop metastasis in its tracks, we need to understand the whole process better, thereby finding the weaknesses and chinks in the tumour.

These results clearly show the important role that S100A10 has in facilitating macrophage activity.

Now, S100A10 is a protein and proteins often (but not always, since some of them are currently thought to be undruggable) make very good targets for therapeutic intervention.

Of course, these results clearly need to be reproduced and confirmed by other groups, but if confirmed, they potentially give us some targets to aim at. For example, we could either look at blocking the macrophages in some clever way or target the S100A10 protein directly with a rationally designed targeted therapy. These apparoaches might potentially slow, or even stop, tumour growth.

What if we found some strategies that were effective? Maybe we could take the approach further and actually use it as a prevention strategy in high risk patients to actually prevent the development of metastasis occurring?

Time will tell, but personally, I was rather heartened by the this wonderful piece of research this morning.

References:

Phipps, K., Surette, A., O’Connell, P., & Waisman, D. (2011). Plasminogen Receptor S100A10 Is Essential for the Migration of Tumor-Promoting Macrophages into Tumor Sites Cancer Research, 71 (21), 6676-6683 DOI: 10.1158/0008-5472.CAN-11-1748

A year in the life of Pharma Strategy Blog

By MaverickNY on October 31, 2011

Last week brought the first anniversary of this blog since moving to WordPress as a platform, but as luck would have it, I was snowed under with more work than usual.

Several people have asked about the stats here recently, so it seems a good time as any to do an annual review. Although this blog has been up and running since 2006, it only started on WP on October 24th 2010.

In the last twelve months, PSB has seen the following activity:

614K reads, with around 50-60K reads per month
337K visitors, approx. 30K visitors per month

The busiest day was 6th June, with nearly 5K reads, thanks to a kind link from Matt Herper of Forbes Health. Ironically, the interim and eagerly anticipated MDV3100 phase III data from Medivation is now due before the end of the year. More on that when the announcement comes out!

What were the most popular posts? Here’s the Top Ten on Pharma Strategy Blog from the last year based on hits:

In some ways, the popularity of these particular posts are no surprise, since if you asked me to name the hot topics in oncology this year, I would have said:

ALK in lung cancer
BRAF and CTLA4 in melanoma
Abiraterone in advanced prostate cancer
ADCs and brentuximab

It wasn’t all positive though, as the ongoing PARP story has been notable largely for the negative data. That may change in the future as scientists and clinicians grapple with finding the right targets and sub populations to aim these therapies at.

I was particularly pleased to see that PI3K resonated with the audience as this one of my favourite pathways, although we still have a long way to go to crack the nut with this target.

A big thank you to everyone who read PSB, posted comments, shared articles or the many email exchanges that have taken place; it is much appreciated and I hope that you have enjoyed reading my thoughts and commentary.

Come December, I will post the annual review and predictions for 2012, but in the meantime, normal blog commentary on cancer related topics will resume tomorrow.

Beautiful

By MaverickNY on October 31, 2011

Perhaps one of the most beautiful articles I’ve ever read on the internet:

“We all — in the end — die in medias res. In the middle of a story. Of many stories.”

You might want to have some tissues handy before reading.

Update on EGFR resistance in lung cancer: new directions

By MaverickNY on October 25, 2011

This morning I was reading a fascinating paper on lung cancer and one of my favourite proteins, CRKL, from the group of prolific lung researchers at Mass General, Dana Farber, MIT and the Broad Institute in Boston:

“Over-expression of CRKL in immortalized human airway epithelial cells promoted anchorage-independent growth and tumorigenicity. Oncogenic CRKL activates the SOS1-RAS-RAF-ERK and SRC-C3G-RAP1 pathways. Suppression of CRKL in NSCLC cells that harbor CRKL amplifications induced cell death.”

Cheung et al., (2011)

We also know that one of the mechanisms of resistance to gefitinib is over-expression of CRKL in EGFR-mutant cells by activating ERK and AKT signaling.

What was interesting about this research was the observation:

“We identified CRKL amplification in an EGFR inhibitor-treated lung adenocarcinoma that was not present prior to treatment.”

Emphasis mine.

We do know that:

Adaptive resistance to treatment is a common problem with kinase inhibitors
Some lung cancer tumours acquire the T790M mutation, which is known to confer resistance to EGFR therapies
Several groups have also reported other known resistance mechanisms may also occur with the EGFR T790M mutation, including MET amplification and CTNNB1 (β-catenin) mutations.

Cheung et al., (2011) tested to see if the PI3K-AKT pathway was specifically involved with CRKL resistance:

“We examined whether treatment with the PI3K inhibitor GDC-0941 suppressed growth of CRKL–over-expressing HCC827 cells in response to gefitinib. Cells were exposed to GDC-0941 alone or in combination with gefitinib. Combined treatment with GDC-0941 and gefitinib resulted in a substantial decrease in the relative proliferation of CRKL–over-expressing HCC827 cells compared to gefitinib treatment alone.”

The answer was yes, activation of PI3K-AKT signalling contributes to CRKL-induced EGFR inhibitor resistance.

It would therefore be very interesting to see what happens in the clinic to a subset of lung cancer patients with CRKL amplification who are treated with an EGFR and PI3K inhibitor to see if this reduces resistance to treatment and improves outcomes. Trials with the combination are indeed ongoing, although I think they are in a more general population of patients with EGFR driven lung cancer. Based on these findings, a subset analysis might prove to be rather instructive here.

What do these results mean?

This study strongly suggests that CRKL may well be a valid therapeutic target:

“These observations show that CRKL over-expression induces cell transformation, credential CRKL as a therapeutic target for a subset of NSCLC that harbor CRKL amplifications, and implicate CRKL as an additional mechanism of resistance to EGFR-directed therapy.”

“Although CRKL amplifications occur in a relatively small fraction of NSCLC, the finding that a similar fraction of NSCLC with translocations involving ALK respond to treatment with crizotinib indicates that targeting genetic alterations present even in a subset of NSCLC may have clinical importance.”

The general idea that CRKL could act as an oncogene in other cancers with CRKL amplifications is also an intriguing idea that needs be explored further.

The paper is very well written and worth checking out for those interested in EGFR mutations, resistance to therapy and development of new therapies.

References:

Cheung, H., Du, J., Boehm, J., He, F., Weir, B., Wang, X., Butaney, M., Sequist, L., Luo, B., Engelman, J., Root, D., Meyerson, M., Golub, T., Janne, P., & Hahn, W. (2011). Amplification of CRKL induces transformation and EGFR inhibitor resistance in human non small cell lung cancers Cancer Discovery DOI: 10.1158/2159-8290.CD-11-0046

Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, & Jänne PA (2007). MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science (New York, N.Y.), 316 (5827), 1039-43 PMID: 17463250

Sequist, L., Waltman, B., Dias-Santagata, D., Digumarthy, S., Turke, A., Fidias, P., Bergethon, K., Shaw, A., Gettinger, S., Cosper, A., Akhavanfard, S., Heist, R., Temel, J., Christensen, J., Wain, J., Lynch, T., Vernovsky, K., Mark, E., Lanuti, M., Iafrate, A., Mino-Kenudson, M., & Engelman, J. (2011). Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors Science Translational Medicine, 3 (75), 75-75 DOI: 10.1126/scitranslmed.3002003

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Update on cabozantinib in medullary thyroid cancer

By MaverickNY on October 24, 2011

This morning, Exelixis announced results from the cabozantinib phase III EXAM trial in medullary thyroid cancer (MTC). I last wrote about this compound as XL184 in MTC three years ago in the phase I trial, so it’s definitely time for an update! A lot has happened since then, including BMS, Exelixis’ then partner, deciding not to pursue the agent’s development.

With a new announcement today from Exelixis, it now appears that median progression free survival (PFS) in the phase III trial, based on a planned interim analysis, was superior in the cabozantinib arm compared to that of placebo. Topline analysis yielded an improvement of 7.2 months (11.2 months versus 4.0 months, HR=0.28, p < 0.0001). The primary endpoint was PFS and no overall survival (OS) is yet available.

A meeting with the FDA is no doubt planned in the light of the interim findings:

“Exelixis will consult with the FDA to determine whether the trial conduct should be changed as a result of these data in conjunction with the SPA. The company is requesting permission to begin a rolling submission of the New Drug Application (NDA) for cabozantinib in this indication to the U.S. Food and Drug Administration (FDA).

It is anticipated that the filing will be completed in the first half of 2012.”

However, if the DSMC do recommend crossing over to cabozantinib, we likely won’t know if patients will live longer (OS). This is always the conundrum with PFS as a primary endpoint in clinical trials.

Earlier this year, the FDA approved AstraZeneca’s vandetanib (Caprelsa) in MTC, the first therapy approved for this indication. Vandetanib differs from cabozantinib in that it is a dual VEGF-EGFR inhibitor, whereas cabozantinib targets MET, RET and VEGFR2. While it was encouraging to see a new targeted therapy available for MTC, vandetanib has some challenges, namely prolongation of QT, causing irregular heart beat and thus it was made available under a Risk Evaluation and Mitigation Strategy REMS agreement. This essentially means that only certified prescribers can prescribe Caprelsa under a restricted program.

That said, many will be interested in how these drugs compare, although it should be noted that it appears the cabozantinib EXAM trial included patients with progressive disease at screening, whereas vandetanib did not. If that was the case, then one would therefore expect the PFS to be shorter in the cabozantinib trial.

According to the April FDA press release, the efficacy data for vandetanib was as follows:

“Median progression-free survival was 16.4 months in the placebo arm and at least 22.6 months in the vandetanib arm. It is too early to determine the median progression-free survival in patients treated with vandetanib or to tell whether they will live longer (overall survival) compared to patients treated with placebo.”

Overall, I think these are encouraging results for patients with MTC, although perhaps the absolute PFS values are a little shorter than I was expecting, but if the side effect profile does not require a REMS strategy as per vandetanib, which is arduous for both physician and patient in terms of monitoring, then that would certainly be a big plus for cabozantinib.

I look forward to hearing the progress of the upcoming meeting with Exelixis and the FDA.

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