Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘hypoxia’

Scott Eliasof, Ph.D VP of Research at Cerulean presents at Molecular Targets press briefingBoston – at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference today we heard about CRLX101 (Cerulean Pharmaceuticals), a nanopharmaceutical in phase 2 development. The presentation highlighted the challenges and opportunities in cancer drug development.

This post is not intended to be a detailed review of the preclinical data presented, but offers a summary of the value proposition, the intended target and the insights we took away from a press briefing at the conference.

Cerulean Pharmaceuticals: Abstract B1, Synergistic activity of CRLX101, a nanopharmaceutical in phase II clinical trials, with antioangiogenic therapies mediated through Hypoxia-inducible factor (HIF) 1 alpha inhibition: A translational research program.

Scott Eliasof, Ph.D. VP of Research at Cerulean Pharmaceuticals presented preclinical data that showed CRLX101:

  • inhibits HIF-1α in multiple tumor types
  • inhibition of HIF-1α is maintained for more than one week after a single dose
  • inhibits HIF-1α and prevents the stimulation of HIF-1α by anti-angiogenic drugs
  • is synergistic with anti-angiogenic drugs
  • inhibits cancer stem cells

Combination trials are planned or starting soon in relapsed ovarian cancer with bevacizumab and in neoadjuvant tolorectal cancer in combination with radiation (CRT). In renal cell carcinoma (RCC) efficacy has been seen even in patients progressing through prior VEGFR therapy.

Challenges: HIF-1α is not has not yet been shown to be a validated cancer drug target.

It is not [a validated target] at this point. A lot of preclinical data suggest that HIF-1α plays an important role in a number of different pathways but since HIF-1α has really been undruggable up until now, the clinical data simply does not exist to really show that this is happening. There are also not good biomarkers yet for HIF-1α,” said Eliasof.

The challenge that CRLX101 faces is to better than the current standard of care in the indications it targets. A trial in non-small cell lung cancer was stopped earlier this year. As Eliasof noted, “we decided strategically at this point in time not to purse it since we couldn’t see something that was dramatically better.”

Opportunities: There is scientific rationale for targeting HIF-1 alpha in renal cell carcinoma (RCC). However, RCC is a crowded space, haunted by the ghost of AVEO.

“Not sure if we are actually going to pursue [RCC] in the long-term at this point in time but it seemed like a really good indication to pursue proof of concept for a HIF-1α inhibitor,” said Eliasof.

Whether combining CRLX101 with bevacizumab in ovarian cancer will lead to an increase in overall survival remains to be seen given the lack of success with this measure with VEGF inhibitors. It is hard to see how adding CRLX101 will shift the survival curve significantly to the right, especially in light of the AURELIA trial data for bevacizumab (Avastin) in ovarian cancer that was presented recently at ECCO 2013 in Amsterdam.

We were left with the impression that this was a “suck it and see” strategy without a clear rationale as to why resistance was occurring in ovarian cancer and whether this approach would logically help overcome it. The data presented today was not entirely convincing that this will be seen, but as Eliasof stated, “we will see” and it is of course possible that CRLX101 may lead to a survival advantage in combination with bevacizumab, but I would not bet money on it.

Today’s press briefing by Cerulean Pharmaceuticals highlights the need for companies to have a solid scientific rationale and development strategy when going after novel drug development targets that so far have proved undruggable. While RCC may have some potential, the market opportunity is small.

It remains to be seen whether there are opportunities for CRLX101 in combination with other drugs, but none of the data presented today was compelling. Instead we were left with the impression of a VC funded company throwing mud to the wall in the hope that something sticks. That’s not the way to approach cancer drug development.

Update: Oct 22, 2013 Is HIF-1α Ready for Prime Time?

If you are in Boston for the Molecular Targets meeting (#targets13) and have an interest in HIF-1α as a target then you may be interested in a symposium (looks like registration is free) taking place later today at Harvard Medical School. Here’s a link to the meeting program and registration.


At the recent ARVO meeting, one of the symposia that I live tweeted from was on “Nanotechnology for Drug and Gene Delivery.”  During his presentation on “Nanomedicines: From Bench to Bedside” Vladimir Torchilin from Northeastern described how nanotechnology can use methods from other scientific disciplines including layer-by-layer (LbL) polymer chemistry.

Which leads me into an interesting paper that came across my desk from Zhiyong Poon and colleagues at the Koch Institute for Integrative Cancer Research at MIT.

In their paper published online on April 23, 2011 in ACS Nano. they describe how nanoparticles with a pH-sheddable layer can be used to target tumor hypoxia.

In other words, the nanoparticle can travel in the blood to the tumor, then in the changed acidity and pH of the tumor microenvironment, the outer stealth layer is eroded and shedded, exposing another layer of the nanoparticle that delivers drug to the target hypoxic tumor region.

Image Source:  ACS Nano. The author’s conclusion is that “this concept for tumor targeting is potentially valid for a broad range of cancers, with applicability for therapies that target hypoxic tumor tissue.”

This proof of principle research is further progress towards the development of nanomedicines in oncology.

ResearchBlogging.orgPoon, Z., Chang, D., Zhao, X., & Hammond, P. (2011). Layer-by-Layer Nanoparticles with a pH-Sheddable Layer for Targeting of Tumor Hypoxia ACS Nano DOI: 10.1021/nn200876f

I have a long-standing interest in hypoxia (lack of oxygen). Many years ago while completing my Masters degree in human physiology, I undertook research at the RAF Institute of Aviation Medicine at Farnborough on the effects of mild hypoxia on pilot performance.

So I was interested to read an article in the February 17, 2011 issue of the New England Journal of Medicine (NEJM) on hypoxia and inflammation, and how this influences disease.  Inflammation is one of my blog themes for 2011, and in a previous post, I wrote about how its ubiquitous role has been characterized as one of the “Insights of the Decade”.

In the NEJM article on mechanisms of disease, the authors Holger Eltzschig and Peter Carmeliet discuss the cross-talk between hypoxia and inflammation, and how this is implicated in cancer, infections and inflammatory bowel disease.

A lack of oxygen (hypoxia) is something that humans are acutely aware of.  We are all familiar with the flight/fight response that is designed to increase oxygen delivery to the brain and muscles.  Hypoxia can also lead to an inflammatory response.  The flip side is also true, where there is inflammation there is often local tissue hypoxia. An example of this is in solid tumors where the level of oxygen is considerably lower than in normal tissue.

The link between hypoxia and inflammation is regulated by the hypoxia-inducible transcription factor (HIF) that is activated by hypoxia. HIF has two subunits HIF-α (consisting of HIF-1α and HIF-2α) and HIF-β. The article goes into detail (beyond the scope of this blog post) about the interaction between HIF and the nuclear factor kappa-B (NF-κB ) transcription factor that regulates inflammation.

Elevated levels of HIF-1α and HIF-2α correlate with cancer deaths.  HIF-1 overexpression is associated with tumor growth, vascularization and metastasis. This has led to HIF-1 being evaluated as a target for anti-cancer drugs.

EZN-2968, a novel HIF-1α antagonist is in phase I clinical trials.  It is a joint development of two biopharmaceutical companies, Enzon in New Jersey and Santaris pharma in Denmark.

It will be interesting to see whether targeting hypoxia dependent signaling pathways will enable a clinically significant reduction in the inflammatory response.

error: Content is protected !!