CALA management, unfortunately subpar 2.1 | CALA Message Board Posts

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Msg  2684 of 2688  at  7/2/2019 4:46:52 PM  by

logansdad


CALA management, unfortunately subpar 2.1

Setting aside the management discussion, below is what's interesting about the science. In particular, the glutaminase inhibitor.
 
One of the difficulties of how we "fight" cancer is the notion of whatever shrinks the primary tumor is likely controlling cancer & extending life. Unfortunately, cancer has proven many times over that is not the case & metastases are the real killers. Clinical trials could be far more impactful if they were designed to eliminate or control the metastases. But there's great difficulty in designing such a trial -basically proving a NULL assumption(until a metastatic site becomes evident, it is not a metastasis). While PFS & OS are common endpoint measures in oncology clinical trials, there is massive skepticism of any therapy which does not by itself show marked shrinkage of the primary tumor. In the case of CALA's glutaminase inhibitor, that skepticism shows up any time they share data -ex: 1) Phs II ENTRATA data called into ? on low PFS on both 839 & control & 2) Nov '17 SITC data (radiographic progression on Opdivo mono & later shrinkage w/combo was called out as "pseudoprogression" on monotherapy).
 
CALA management pushes forward w/the notion that CB-839 is shrinking the primary tumor by "starving" primary tumor cells while simultaneously allowing immune cells to access those same nutrients the cancer cells cannot access due to CB-839. Management posits that in turn, this synergizes w/certain other therapies dependent on mechanism of action. There is validity to this notion but seems marginal given the data thus far. The more extraordinary impact of the 839 molecule is on the cancer's metastatic potential.
 
Stepping back & thinking about the Hippo pathway(YAP/TAZ) and its critical role in tumor formation, progression, and metastasis https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923370/, there's a certain value to targeting this pathway. Based upon work done a few years ago, solid evidence exists that 839 can disrupt YAP/TAZ activation https://www.jci.org/articles/view/86387 But disrupting YAP/TAZ activation would not have a dramatic impact on shrinking the primary tumor, nor would its impact be substantial in late-line therapies. But what might show up is surprisingly stable disease & disease control rates(DCR).
5/13/19 OncLive intrvw on RCC treatment paradigm -highlights 1st "trial with cabozantinib with [CB-839], a glutaminase inhibitor; it is impressive that there is no increase in toxicities but there is a great disease control rate." https://www.onclive.com/web-exclusives/rcc-paradigm-continues-to-rapidly-develop-with-tkiio-combos
For what it's worth, CALA's focus on RCC for 1st approval does appear valid as relates to disrupting YAP/TAZ activation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4101344/
 
Considering the clinical data thus far from 839, DCR has been notable in nearly every case. Whereas tumor shrinkage...interesting, just not overly compelling. This was also the case in monotherapy studies. The likely reason for this is the metabolic flexibility of established tumor cells & the more stringent metabolic requirements at tumor formation(primary or metastatic site) & near the periphery of the primary tumor -likely having to do w/the critical aspect of changes in cell morphology https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709733/.
While there's an imperfect understanding of cell morphology & cancer, there is a good deal of evidence to suggest morphology is important. In particular, the fibrosis of the cell http://clincancerres.aacrjournals.org/content/20/14/3637 and characteristics of the surrounding tissue https://advances.sciencemag.org/content/4/1/eaao4881.full In that context YAP is quite important https://www.gastrojournal.org/article/S0016-5085(18)30002-7/pdf https://www.gastrojournal.org/article/S0016-5085(18)30259-2/pdf And YAP/TAZ was recently found to have a role in cell morphology https://www.biorxiv.org/content/biorxiv/early/2019/01/23/528133.full.pdf
 
So if CALA can successfully pursue the science, CB-839 could have an "evolutionary" effect on the treatment for individual patients. However, it's relatively benign side-effect profile gives it the potential to have a "revolutionary" effect on the treatment of cancer -opening the door wider to some cancers becoming a chronic disease.
 
The majority of researchers today approach cancer as a "genetic disease" -assuming a singular genetic event leads to a normal cell becoming cancerous. This wasn't always true https://www.newyorker.com/magazine/2017/09/11/cancers-invasion-equation Even with all its detail, the genetic model still gets us almost nowhere as far as what actually causes cancer. Science can tell us what is associated w/cancer https://www.niehs.nih.gov/health/materials/cancercausing_viruses_508.pdf but not what actually causes the cancer https://www.forbes.com/forbes/2009/1102/health-cancer-tonsils-virus-hpv-at-our-throats.html#16d9df2f29ec i.e. the "event."
But take a step back & start over. First, allow that certain conditions(ex: cancerous microenvironments) might be better than others for a cancer cell to initiate/survive/metastasize. Second, allow that genetic mutations can occur w/in the cells that exist w/in those cancerous microenvironments. Third, allow that those cancerous microenvironments occur as a result of the body's response to some sort of insult -be it continuous exposure to UV rays, continuous exposure to smoke, exposure to a virus, exposure to radiation, etc. Fourth, allow that genetic mutations can occur regularly in our cells but may not proliferate w/out the generosity of a cancerous microenvironment. Fifth, allow that cancerous microenvironments can occur in multiple locations w/in the body but how various classes of cells(say lymphatic cells) respond to insult determines where those microenvironments might be. -You now have a model which might better explain the #s that we see in cancer, the metastases(sites, #s) that we see, the challenge of complete response, the inability of radical mastectomy to resolve a cancer, the changing landscape of what causes certain cancers, the frequency of recurrence, and the dreaded diseases that are "cancer."
Recent work suggests links between cellular metabolism & gene expression https://www.technologynetworks.com/immunology/news/t-cell-signalling-affected-by-glutamine-311353
 
Net, CALA is @ the nexus of a potentially interesting step forward in the treatment of cancer. For the sake of many stakeholders(cancer patients) let’s hope they do better with the science than with their investors.


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Replies
Msg # Subject Author Recs Date Posted
2685 Re: CALA management, unfortunately subpar 2.1 wilderguide 3 7/2/2019 5:24:24 PM
2686 Re: CALA management, unfortunately subpar 2.1 logansdad 3 7/8/2019 2:20:02 PM


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