Biotech Strategy Blog

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

Posts tagged ‘Cancer’

Scaling the ramparts in Real Madrido

It feels slightly surreal to be writing about this year’s annual ESMO confab instead of attending in person in Madrid, Spain.

While much of the time and attention at ESMO is usually focused on the major phase 3 readouts from various clinical trials, we will be covering these during the meeting as they are presented to avoid repetition since many of the topline company trial results have already been announced.

In this year’s conference Preview series, I wanted to take a step back and explore early new product development in several forms:

  • Biomarkers and potential new ways of predicting outcomes in development
  • Emerging novel targets of interest
  • Developmental therapeutics – trials and tribulations

This initial review will tackle some important developments pertaining to various biomarkers of interest.

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This is the penultimate post in our mini-series looking at the potential of immunometabolism for cancer new product development. The initial plans for six posts ended up being revised with a seventh and final article based on an additional thought leader interview.

What’s the immunometabolism prize?

Like a series of postcards from our travels, the aim was to offer a flavor of different approaches in the field, some of which are already being translated and evaluated by biotech companies in clinical trials.

Along the way, like conversations on a journey, we spoke to several scientists working at the forefront of this research. As regular readers know we don’t just interview the ‘great and good’ – the established PI’s but in this series – we also spoke to some emerging up and coming researchers too. Each offered a unique personal perspective on different aspects of metabolism and its potential role in cancer research.

In today’s post, we share an interview with a young researcher working on a novel and intriguing approach, which could improve adoptive cell therapy.

We expect to hear a lot more about many of the immunometabolic strategies we’ve highlighted over the course of coming months, so this is a theme we will return to as new data emerges.

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It’s the dog days of summer in August, traditionally a time when many of us go on holiday and while that’s more challenging in the uncertain times of COVID-19, we at BSB are taking a break for the next three weeks as we recharge/renew for a busy autumn of virtual meetings.

We won’t be writing much about topical news or recent data for the next few weeks, but instead, while we’re taking time out we’ve prepared a six-part mini-series looking at immunometabolism and its potential for cancer immunotherapy.  We’ve run this kind of series every summer over the last couple of years and they’ve worked out rather well.

One of the things we did on Seasons 3 and 4 of the Novel Targets Podcast was to look at topics involving emerging areas of complex research, where we often didn’t know all the answers yet there were emerging data worthy of time and attention. Immunometabolism is certainly a topic which meets those criteria – it’s been on our list to do a deeper dive into for a while and here we are now, with some extended time to make the most of the opportunity to do it some justice.

We’re obviously dating ourselves in that we used to write letters or send postcards to friends and family from our holidays, this mini-series is very much in that style.

To be clear, this is not intended to be a comprehensive review of absolutely everything in the landscape, instead we’ll be reviewing some of the key concepts, showcasing important papers, and highlighting data at AACR20 that caught our attention. There will also be mention of a few emerging biotech companies in the field and for good measure we have three interviews with scientists at the forefront of research, which may have excellent translational potential to the clinic.

By the end of our three-week journey together, hopefully you’ll gain a greater understanding of the new product development potential for cancer immunometabolism and be better placed to put into context new data as it steadily emerges over the coming months.

In this first post, let’s set the scene by looking at immunometabolism and the role it plays in the fate, function, and fitness of T cells.

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We are living in exceptionally challenging times and our thoughts are very much with all those healthcare professionals at the front line in the battle against Covid–19.

For people living with cancer, particularly those who have stage IV disease, the stark reality – in the UK and even some States in the US – is an ICU bed may not be available if they come down with the severe form of the disease.

When it comes to cancer research most labs, with the exception of those working on Covid–19, are now closed, but there is still data coming out to keep us all going as we work from home. ASCO20 will be a virtual meeting this year, while AACR will likely have some virtual presentations later in April. There are also plenty of publications coming out in journals from work already completed.

In this post we’re looking at newly published research and one possible immunological link between inflammation related to cancer and certain infectious diseases.

Last week we spoke to Dr Kamal Khanna (@Kamal_M_Khanna), Associate Professor at NYU Langone about research from his lab, which has just been published in the journal Science Immunology.

Although science is important, what matters most in these exceptional times is making sure everyone comes through it safely. Dr Khanna kindly spoke to BSB under embargo on Wed 25th March, where we also spoke about the surreal experience going on around him as we asked, how are things going with you in New York?

“It’s crazy. This has become the epicenter now. It just moved so fast here from having no cases and everyone wondering what’s going on to just explosion. Lab is shutdown, unfortunately. They’re allowing one person to go in at one time, in my lab just to maintain mouse colonies and do very limited experiments.

They’re allowing us to do the Covid–19 experiments, which we started just a few days ago, but also in a limited fashion. Those are the things we’re doing right now is simply plaquing the virus, and we have a few strains and we’re just testing growing them and so. We’re getting some limited human samples, but probably that will explode now. Our hospital has the most amount of Covid patients, so much so that they just made a makeshift morgue with a tent, unfortunately, right next to where we are.

So that’s the reality of where we are right now and hoping that this will peak at some point, they’re predicting in about 2 to 3 weeks that it would reach its apex and then all the social distancing and things that we’ve been doing, hopefully that will start to bring some of the numbers down, that’s the hope.”

In this post we offer an extended interview with Dr Khanna where we explore possible immunological links between inflammation in relation to cancer and infectious diseases and how research from his lab could generate new insights into cancer, as well as some potential impacts for Covid–19.

If you’d like to read our latest in-depth expert interview on cancer-related topics, please do consider supporting independent science journalism in these challenging and exceptional times.

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In the fourth part of our mini-series in novel targets and agents in development we turn to novel cell therapy approaches that are perhaps under the radar for many observers.

While these might seem bleak times during a pandemic, there’s always a silver lining somewhere

While much attention has been focused on antigen loss or downregulation of the target wih adoptive cell therapies, research continues to evaluate various solutions to the problem.

One obvious way is to develop dual CARs or target multiple antigen targets of relevance to the tumour type being investigated.

There are other potential solutions being looked at, both in preclinical animal models and in translational work using cells from people treated with HSCT or CAR T cell therapies.

Here, we look at an alternative immunotherapy approach, which with time may have utility in both hematologic malignancies, as well as solid tumours…

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We’re living in uncertain and challenging times as the coronavirus impacts healthcare providers around the world and puts them in the front line of exposure.

Meetings are being cancelled or postponed as companies and institutions batten down the hatches and restrict non-essential travel. Nobody wants their employees to bring back an infection, nor does anyone want to be stranded or quarantined in a far-flung place. I expect many hospitals will also want their staff to be readily available as the number of cases escalate in many countries.

We at BSB are also carefully considering our plans and which conferences in coming months we will attend in person, and expect it will be fewer than recent years. We’ve already cancelled attendance at a couple of international meetings and are actively considering whether we will cover others remotely too.

The worlds of oncology and the coronavirus are colliding in many ways, including on the scientific level too.

It turns out that key RNA transcription factors may have a role to play as therapeutic targets for both cancer and the coronavirus.

Science is very much about making connections. In this post, we’re taking a look at one transcription factor that could be a useful target in the context of both coronaviruses and oncology.

It’s time to look through an alternative window and see an entirely different perspective…

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If there is one topic that has proven to be rather controversial over the last decade or so, it has been the CD47 and signal-regulatory protein (SIRPα) pathway.

What originally started out as a basic research project at the NIH and then academia has long since morphed into a highly competitive mini landscape of its own with multiple small and large biotech companies pursuing preclinical and clinical research in the space.

Are they going to be flying high or experiencing a bumpy landing?

In our latest 3-part mini-series, we take a look at the underlying biology, followed by separate posts on the companies in the landscape and finally, a company interview to highlight this growing field of oncology R&D.

We first posted a snippet on this pathway back in 2009 and much has happened since then. How much of the attention is hype over hope? Is the target a valid one? Where is the research heading in 2018 and beyond?

To start the ball rolling, we begin at the beginning with a look at the science…

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As those of you who have been following my conference schedule already know, I will be at Health Journalism 2011 in Philadelphia later this week.  The annual meeting of the Association of Health Care Journalists (AHCJ) runs from April 14-17.

It’s my first time at an AHCJ conference, and in my first video blog post I have shared why I am going and what I hope to obtain from the meeting.

Some of the expert sessions that I am particularly looking forward to are on:

Spotting fraud in scientific research (moderated by Ivan Oransky, M.D. executive editor, Reuters Health; blogger, Retraction Watch and Embargo Watch)

Efforts to revive the drug delivery pipeline (moderated by Ed Silverman, editor-at-large, Med Ad News and R&D Directions)

Understanding nanotechnology’s role in fighting cancer (moderated by Eric Rosenthal, special correspondent, Oncology Times)

Best practices in blogging and social media (moderated by Scott Hensley, health blog writer and editor, National Public Radio)

As William Heisel states in an excellent blog post on Reporting on Health, the journalism stars have come out for ACHJ Health Journalism conference in Philadelphia. I am looking forward to an exciting and informative meeting. Hope to see you there.

 

http://www.youtube.com/watch?v=IjoJ2z_mEvA

Continuing my previous post about emerging drugs for osteoporosis, one of the new classes in development are those that target sclerostin.

Sclerostin is a protein produced by osteocytes within bone that inhibits bone formation. It is thought to pass through the surface of bone where it acts on osteoblasts (cells responsible for bone formation).  There it binds to low-density lipoprotein receptors and inhibits the Wnt/beta-catenin signaling involved in bone mass regulation.

There is some uncertainty in the scientific literature as to the precise method by which sclerostin acts on bone. However, the Wnt/beta-catenin osteocytic signaling does play a role in bone homeostasis.

Preclinical animal work using an antibody to sclerostin led to increased bone formation, bone mineral density and bone mineral strength. This supports the concept that inhibition of sclerostin has potential as a treatment for osteoporosis.

Interest in sclerostin has grown enormously, with over 50 abstracts presented on its measurement at the 2010 American Society of Bone and Mineral Research (ASBMR) annual meeting.  Also last year, Biomedica and its distribution partner ALPCO Diagnostics launched the first commercial immunoassay kit for the measurement of circulating sclerostin.

Not surprisingly companies have started to look at sclerostin inhibition as a drug development target.  The leader in the pack is Amgen with AMG 785, a sclerostin monoclonal antibody.

The phase 1 trial results published by Padhi et al in the January issue of the Journal of Bone and Mineral Research (JBMR) show that it was well tolerated in 72 healthy subjects that received AMG 785 or placebo.

AMG 785 is now in phase 2 clinical trials that will look more closely at dosing and efficacy.  A 330 patient study to assess fracture healing is currently recruiting (NCT01081678).  The study will look at three doses of AMG 785 (70mg, 140mg, 210mg ) given by injection subcutaneously (under the skin).

The study hypothesis is that giving AMG 785 to those with a new hip fracture will increase their healing. The functional healing will be measured using the timed-up-and-go (TUG) test i.e. the time to stand up on one’s own, walk three meters, turn around, walk back and sit down.

The estimated primary completion date for this trial is December 2012, so I don’t expect we will see some data till 2013 at the earliest.

Amgen already has a major osteoporosis franchise with denosumab, it’s RANKL inhibitor for postmenopausal women at high risk for fracture. It’s a smart new products strategy to build on this, although its too early to tell whether AMG 785 will make it to market.

One unknown challenge for those targeting sclerostin’s action is whether disruption of Wnt/beta-catenin signaling in bone could lead to the stimulation of cancers elsewhere in the body, since this pathway is also involved in a wide range of cellular signaling in the body, including cancer.

While this may not be a problem in healthy individuals, it could raise the issue of the use of sclerostin inhibitors in those patients with low bone mineral density (BMD) or fractures who are being treated for cancer at the same time. Since skeletal related events (SRE) are seen in many advanced breast and prostate cancer patients, this may be a cause for concern.

Further information on Pharma Strategy Blog where Sally Church has written an excellent post on “Wnt Signaling and Cancer.”

Update Jan 2, 2014 Phase 2 Data for Romosozumab published in NEJM

New Year’s day is not when you might expect the New England Journal of Medicine to publish an online first article. However, that’s what happened yesterday when the phase 2 trial data for romosozumab (AMG 785) in postmenopausal women with osteoporosis was published. The joy of Twitter is that interesting news is rapidly shared:

The trial data published in the NEJM by McClung et al shows that romosozumab, a sclerostin inhibitor being developed by Amgen/UCB Pharma provides increased bone mineral density and bone formation:

“All dose levels of romosozumab were associated with significant increases in bone mineral density at the lumbar spine, including an increase of 11.3% with the 210-mg monthly dose, as compared with a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide”

In the accompanying NEJM editorial, Carolyn B. Becker MD from Brigham and Women’s Hospital in Boston describes the results as “impressive” and outlines many of the questions that remain unanswered that hopefully the results of the phase 3 trial under way (NCT01631214) will provide.

Whether it is a potential blockbuster as some on Twitter questioned yesterday evening, I think we will have to wait and see what the phase 3 trial data shows in a larger study.

However, based on the phase 2 data published in the NEJM it looks like romosozumab will be a future addition to Amgen’s osteoporosis franchise unless something untoward is seen in the phase 3 trial results.

References

ResearchBlogging.orgPadhi, D., Jang, G., Stouch, B., Fang, L., & Posvar, E. (2011). Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody Journal of Bone and Mineral Research, 26 (1), 19-26 DOI: 10.1002/jbmr.173

Uveal melanoma is a common cancer of the eye that involves the iris, ciliary body and choroid.  It is a disease that hits 2000 people per year in the United States and is common in those over 50.  Standard treatment involves removal of the eye or radiotherapy. There is an unmet need for systemic drug therapy.

Mutations in the BRAF gene (a member of the Raf family that encodes a serine/threonine protein kinase) have been found in many skin melanomas.  In 80% of the cases, a single point mutation in exon 15 (T1799A) has been shown to occur.  Some new agents in development such as PLX4032, ipilumumab, GSK2118436 have shown promise in advanced skin melanoma, but research suggests that BRAF may not be the key to Uveal melanoma.

Henriquez et al, in a paper published in Investigative Ophthalmology & Visual Science showed that the T1799A BRAF mutation was only present in 9 of 19 iris melanoma tissue samples, but only in one case of uveal melanoma, suggesting differences in the genetic and clinical differences between the two.

Recently, two papers have been published that provide new insight into this intraocular cancer. In the December 2, 2010 issue of the New England Journal of Medicine, Van Raamsdonk et al, found mutations of either the GNAQ or GNA11 gene to be present in 83% of uveal melanomas that were sequenced (n=713).

Harbour et al, in the December 3, 2010 issue of Science reported findings of a frequent mutation of BAP1 in metastasizing uveal melanomas. They found that in 26 of 31 (84%) of uveal melanoma tumors they examined, there was a mutation of BAP1, the gene encoding BRCA1 associated protein 1 (BAP1) on chromose 3p21.1. The results published in Science, “implicate loss of BAP1 in uveal melanoma metastasis and suggest that BAP1 pathway may be a valuable therapeutic target.”

The data suggests that there may be multiple pathways involved in uveal melanoma.  It is promising to see translational medicine in action, with scientists seeking to understand the molecular basis of a disease so that targeted therapies can be developed.  Uveal melanoma only strikes a relatively small number of patients, but if a highly effective drug can be developed, this could be a market opportunity worth pursuing.

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