VDP-63 Anticancer and pro-longevity effects of high molecular weight hyaluronic acid (from naked mole rat to human) - Vera Gorbunova

Proposals Passed Proposals
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Longevity Dealflow team

Scientific evaluation: Sebastian Brunemeier, Tim Peterson, Rhys Anderson, Koen De Lombaert

Business evaluation: Sebastian Brunemeier, Tim Peterson

Shepherd/Sourced by: Tyler Stahl

Squad members: Paolo Binetti, Rhys Anderson, Rakhan Aimbetov, Ryan Spangler

Project PI: Vera Gorbunova

Simple Summary

Naked mole rats (NMR) are long-lived rodents with a lifespan of up to 40 years, compared to normal rats which live about 3 years. Unlike other rodents, NMR are found to be cancer resistant. Previous research by the Gorbunova lab has demonstrated cancer resistance in NMR is modulated by the abundance of high molecular weight hyaluronic acid (HMW-HA) in tissues (1). Additional research has demonstrated that transgenic mice expressing naked mole rat hyaluronan synthase gene (NHAS2) have less tumours, improved health, and live 10% longer than mice without the transgene (2). To increase HA in human patients and translate these findings into the clinic, this project will screen and develop small molecule inhibitors of hyaluronidases, the enzymes that break down hyaluronic acid. These compounds can be used for cancer treatment and are expected to increase human healthspan and lifespan.

VDP-45 on Decentralised Tech Transfer outlined a new model of funding which, in collaboration with academic partners, conducts experiments at CRO or “fee-for-service” academic facilities. In brief, DTT allows for greater efficiency with treasury resources, speed of project initiation, and the ability to reward research collaborators for their effort.

VitaDAO is launching a newco with the Gorbunova lab, called Matrix Pharma. A term sheet has been signed, with the deal terms below that entails the incorporation of Matrix Pharma.

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Problem

The overall population is aging, and aging is the major risk factor for nearly all human diseases, e.g., cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, and Alzheimer disease, to name a few. Cancer, specifically, accounted for an approximately 10 million deaths worldwide and had an estimated 19.3 million new cases in 2020 (3).

While cancer progression is predominantly associated with genetic driver mutations, a number of other critical factors have been identified that facilitate cancer initiation and progression, offering new therapeutic opportunities in cancer treatment. The tumour microenvironment is one such component, consisting of tumour cells, tumour stromal cells, endothelial cells, immune cells, and non-cellular components of extracellular matrix (ECM). Through complex signalling networks, tumour cells have the ability to use non-malignant cells to their own advantage, consequently leading to tumour formation and maintenance (4).

HA, a long polysaccharide found in the ECM, plays a multifactorial role in tumour suppression and progression (depending on the polymer size) through interactions with HA receptors such as CD44. HA polymers are degraded by three major hyaluronidases, HYAL 1-3. HYAL2 is specifically located at the cell surface, and together with reactive oxygen/nitrogen species (ROS/NOS), are responsible for breaking down HWA-HA (1-6 MDa) to low molecular weight HA (LMW-HA)(10-250 kDa). Cancer initiation results in changes in HA organisation and processing including increased HA synthesis and expression of hyaluronidases, resulting in the fragmentation of HA. LMW-HA is known to promote neo-angiogenesis, tumor cell migration, invasion, and proliferation. Contrary, HMW-HA promotes tissue homeostasis and prevents tissue metastasis, through CD44 interactions and signalling (5,6).

Opportunity

Using exceptionally long-lived and cancer-resistant animals provides a strategy to identify molecular mechanisms that support longevity and healthspan, potentially uncovering novel targets and/or pathways for translation to humans. NMR, based on their size, would not be expected to live past six years, yet in some cases, live beyond 30 years. NMR also rarely get cancer, are resistant to some types of pain, and can survive up to 18 minutes without oxygen. At advanced ages, their mortality rate remains lower than any other mammal that has been documented. As such, the NMR’s biology has garnered great interest from ageing researchers.

Based on published work by the applicant, where it was found that NMR cancer resistance is conferred by abundant HMW-HA in tissue (1), the authors propose to design inhibitors against hyaluronidases, the enzymes that normally degrade HA. Furthermore, very-high-molecular-weight HA (vHMW-HA) has superior cytoprotective properties compared to the shorter HMW-HA, protecting both human and mouse cells from stress-induced cell-cycle arrest and cell death (7).

Most recently, the Gorbunova lab has found that transgenic mice that express the NMR hyaluronan synthase gene have less cancer, show improved health, and live 10% longer than mice without the transgene, supporting that higher levels of HA promote healthy living and longevity (2). While humans cannot produce vHMW-HA, it is possible to increase HMW-HA and decrease LMW-HA by inhibiting the enzyme that breaks hyaluronans down, namely hyaluronidase 2 (HYAL2). The aims of the proposed studies now intend to develop and validate HYAL2 inhibitors in order to translate these research findings into clinical applications.

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IP Roadmap

The Gorbunova lab has designed a complex and validating functional screening assay to find inhibitors of hyaluronidase 2 (HYAL2). A previous ~3k compound screen has led to discovery of one natural product that increases the levels of HA in mouse and human tissues. IP will include formulations and/or modifications of this natural product. Within the framework of the present proposal the team plans to perform larger compound high throughput screen (HTS) with the proprietary HYAL2 inhibition assay and medicinal chemistry optimization of hits to produce patentable new chemical entities.

Budget

A financing of USD 300k provided by VitaDAO, with 200k allocated to HTS and exploratory medicinal chemistry with a 3rd party CRO or academic ‘fee for service’ facility, and 100k allocated to the Gorbunova lab for hit compound experiments.

5k/month will be allocated towards consulting agreement

Program 1: HTS and med chem for new HYAL2 inhibitors

Phase 1: High Throughput Screening (HTS) – $100k
Phase 2: Medicinal Chemistry on hits – $100k

Program 2: Validation of existing in vivo active HYAL2 inhibitor (EC50 ~ 20 µM)

Administration of hit compound to mouse models of cancer to test for curative and
preventative effects - $100k

Funds will be used to assist in cover the costs related to:

Technician effort
Mouse cost
Chemical cost
Culturing human cancer cell lines for xenografts
Mouse evaluation for tumour burden

Milestones/Endpoint

Milestones to be agreed in separate full length R&D plan.

Team

Vera Gorbunova, PhD

Vera Gorbunova is an endowed Professor of Biology and Medicine at the University of Rochester and a co-director of the Rochester Aging Research Center. Her research is focused on understanding the mechanisms of longevity and on the studies of exceptionally long-lived mammals. Dr. Gorbunova pioneered a comparative biology approach to study aging. She elucidated the mechanisms that control evolution of tumor suppressor mechanisms. She uncovered the function of the longevity gene Sirtuin 6 in regulating genome stability across species. She demonstrated the role of transposable elements in driving age-related inflammation. Her work received awards from the Ellison Medical Foundation, the Glenn Foundation, AFAR, and NIH. Her work was recognized by the Cozzarelli Prize from PNAS, prize for research on aging from ADPS/Alianz, France, Prince Hitachi Prize in Comparative Oncology, Japan and Davey Prize from Wilmot Cancer Center.

Highlights

  • A novel idea from a world-leader in the field with extensive experience in longevity and healthspan mechanisms
  • Strong published and supporting evidence for the target.
  • May work against many types of cancer – high impact
  • May address other Extracellular Matrix (ECM) and skin-related conditions, as well as: wound healing, arthritis and joint conditions
  • Validated tool compound identified – showing that this target is druggable
  • Strong IP potential with possible novel chemical matter (to be identified).

Risks

  • Hyaluronidase inhibition may not be effective to improve health - most clinical hyaluronic acid data is limited to dermatology (skin aging), so unclear if it would work systemically to increase life/health span and reduce cancer in humans.
  • Very novel and therefore still high-risk.
  • Mixed literature evidence on the role of hyaluronan in metastasis.
  • Expressing more NHAS2 enzyme (increased synthesis) is not entirely equivalent to reducing catabolism (HYAL1/2i). The authors previously published (Takasugi et al., 2020) that several cytoprotective effects of hyaluronic acid are driven specifically by vHMM-HA (>6MDa), which may be dependent on two naked mole rat-unique amino acid variations in the active site of hyaluronan synthase 2 (HAS2) and thus may not able to be produced in human cells even with hyaluronidase inhibition.
  • Potential impact on the efficacy of chemotherapy and immunotherapy if taken in combination

Senior Reviewers

This proposal has been reviewed by 8 senior reviewers, including: scientists, biotech business experts, a venture capitalist, and an MD.

Qualitative Evaluation

The PI is a world leader in the field of comparative biology with a focus on longevity and healthspan mechanisms. They propose a unique approach with relatively little competition on the MoA and a straightforward road to NCE IP. There is strong published and supporting evidence for the target in mice. The mechanism for cancer prevention seems to be well established via CD44. There is already a screen hit with a potential asset in hand. This could be a first DeSci project, where the DAO is spinning out the company and that is a step forward for the community.

However, the hyaluronan role in cancer is somewhat controversial: on one hand, HMW-HA production is linked to cancer resistance, on the other hand, HMW-HA is involved in driving and maintaining malignant progression. The underlying hypothesis needs more PoC data to be further substantiated. It is unclear if the proposed intervention would work systemically to increase life/health span and reduce cancer in humans. No detailed plans are presented. The project is early and very high risk, but no insurmountable weaknesses.

Quantitative Evaluation

The reviewers have scored the proposal on different aspects including general conviction, on a scale of 1-5 (with 5 being the highest). Here are the average scores:

  • Novelty: 4.3
  • Feasibility & Data: 3.5
  • Relevance: 4.6
  • Science Team: 4.6
  • Market Advantage: 3.5
  • IP Potential: 3.7
  • Conviction score: 4.3

References

  1. Tian X, Azpurua J, Hine C, et al. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature. 2013;499(7458):346-349. doi:10.1038/nature12234
  2. Zhang Z, Tian X, Lu JY, Boit K, Ablaeva J, Tolibzoda Zakusilo F, Emmrich S, Firsanov D, Rydkina E, Biashad SA, Lu Q,Tyshkovsky A,Gladyshev VN, Horvath S, Seluanov A, Gorbunova V. Naked Mole-Rat Hyaluronan Synthase 2 Promotes Longevity and Enhances Healthspan in Mice. Preprint posted online August 8th, 2022. doi:10.2139/ssrn.4185135
  3. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660
  4. Baghban R, Roshangar L, Jahanban-Esfahlan R, et al. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun Signal. 2020;18(1):59. Published 2020 Apr 7. doi:10.1186/s12964-020-0530-4
  5. Gorbunova V, Takasugi M, Seluanov A. Hyaluronan goes to great length. Cell Stress. 2020 Jul 17;4(9):227-229. doi: 10.15698/cst2020.09.231.
  6. Liu M, Tolg C, Turley E. Dissecting the Dual Nature of Hyaluronan in the Tumor Microenvironment. Front Immunol. 2019;10:947. Published 2019 May 10. doi:10.3389/fimmu.2019.00947
  7. Takasugi M, Firsanov D, Tombline G, et al. Naked mole-rat very-high-molecular-mass hyaluronan exhibits superior cytoprotective properties. Nat Commun. 2020;11(1):2376. Published 2020 May 12. doi:10.1038/s41467-020-16050-w
  • Agree
  • Agree with revisions (please comment)
  • Disagree

0 voters

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Excellent write up @tylerstahl !! This needs milestones and timeline to achieve payouts. Also the $ quoted should be “up to”. If HTS doesn’t cost $100K, VitaDAO shouldn’t feel obligated to spend $100k. Similarly, some clarity around how long the $5k/month consulting arrangement is expected to last before a new fundraising should be described. In general, I’m still under the impression we can do the project more cheaply than what’s described here.

In summary, the $ allocated needs to be further specified such that VitaDAO token holders have confidence the money will be used wisely.

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I think the HTS is premature-- if the existing active inhibitor does not work, the whole project is dead in the water.

Given the later publications from the PI’s lab, HA is at best one part of a much bigger picture. I am skeptical that an HA inhibitor will work in any real cancer model. DNA integrity is expected to be a bigger part of cancer resistance.

It’s unclear which mouse cancer model will be used, and how far VitaDAO plans to take the IP. The community should be aware of these plans, so they can vote accordingly. For example, there are 14 day tumor models that poorly translate to humans, but get used to hype projects to be sold before the whole house of cards comes crashing down (preferably after the big grant, publication, or sale). What is VitaDAO’s primary end goal? How does VitaDAO prioritize the following goals of this research: flip a biotech prior to Phase 1 to show an early win, onboard a prominent PI/university for better visibility, or pursue a new anti-cancer approach?

This is a well-funded PI who should be able to generate proof of principle with existing resources. If the PI is not willing to take the risk with existing resources, it tells you that the PI believes this a long-shot at best.

At minimum, I think VitaDAO should ask to see purity of the natural product, and that the natural product works in a mouse tumor model (or xenograft) before pursuing this idea any further. Works is defined as no overt toxicity from the product, and the product eliminates or prevents the tumor. Pilot study with 3-5 mice/group would be fine for this. Dosing and route whatever the PI (and IACUC) wants, as long as dose is reasonable for translation to human. Full PK would only be relevant if it shows efficacy.

Since this is a small pilot experiment that a tech or trainee could do in addition to existing work, I think $10-$20k would be a reasonable initial investment, depending on the cost of getting enough natural product to stick into mice (and if the product is too expensive to produce/isolate, that will kill the biz end later anyways). If the PI is unwilling to contribute tech time to generate pilot data, this is not a project the PI expects to succeed. With $10-$20k, the PI would have the flexibility to try a few models and dosing strategies in case the first try or two failed.

If the pilot study fails, VitaDAO limits the loss to 5% of the initial proposed amount. If it succeeds, then those data would justify a more elaborate proposal.

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Per @longevion, I had the wrong settings for the poll. Once I have the correct markdown command, I will reopen the poll.

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Okay the poll should be corrected. Apologies for any confusion

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Thanks @tylerstahl

@everyone please vote again

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The PI has agreed to perform additional experiments in her lab with the natural product hit compound, and a pilot cancer model is certainly on the table. Which model would you like to see?

There is unpublished target engagement data from this NP, but the compound is not very potent. Finding more potent HYAL2i would be wise. Perhaps a member of the deal team can share this data on the NP with you.

This target has been well supported in the oncology literature, but these animal models of cancer like xenografts are not very reliable. There are many applications for a HYAL2i inhibitor beyond oncology, and a drug-like HYAL2 inhibitor has not been made, to our knowledge.

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For initial proof of concept, I’m not married to any particular model, as long as it looks good. Depending on their conviction, trying a couple models might be needed. All the models have pros and cons. I would expect a shorter model for the initial study to justify the time and effort going into longer/better models and/or improving the drug. Since it inhibits hyaluronidase, I would assume a metastatic model would be most likely to show efficacy. Counting lung mets from B16 melanoma model is reasonably straightforward. Or everyone likes triple negative breast cancer for invasion.

If there are other applications beyond oncology, those should be considered seperately on their merits. If those applications are more likely to succeed than oncology, the proposal should be refocused to those.

Given the shortened time frame for patents on small molecules in the US, they may also need to think about how to priortize the potential applications.

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Do we have any sense of a clinical strategy here? What tumor types do we think are the most promising and is there any evidence of where to take any hits we find?

How are we doing diligence on CROs also to perform HTS? Who are the CROs under consideration to run each of these initiatives and how many compounds are included in the screen?

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Thoughts on traunching this into 3x 100k phases?

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Specifics of clinical strategy tbd.

We have talked to a few CROs. We are looking to conduct the screen at a core facility at Washington University. We can include further details of the screen in the R&D plan

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Thanks for the extra detail. I feel like we should consider more than one CRO. Would it be beneficial to use a service like https://www.cro-matic.com/ could help us identify the highest-value CRO

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agree, great idea in general to get most cost competitive quotes

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Hello, this is a great proposal and a great idea!
Our team also works on the involvement of ECM in aging, and I have a couple of questions.
You showed that HMW-HA slows down tumor progression in NMR, and mechanoreception and ECM molecules play an important role both in tumor growth (in terms of cell proliferation) and in metastasizing. Do you think HMW-HA would work as a growth suppressor or rather a metastasis suppressor, or maybe both? Would you track both in your animal model? Addressing these questions might be out of the scope of the current project, but it may be beneficial if you decide to continue developing the HMW-HA as an anti-cancer agent.
Also, during your screening for hyaluronidase inhibitors by any chance did you check any flavonoids?

Sincerely

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Excellent comments. I was thinking along similar lines - this is an interesting MOA but will it have the horse power to provide single agent activity - this is currently the bar for moving forward (even preclinically) in oncology development.

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Is this MOA thought to be protective for oncology or is there a role as a therapeutic in cancer patients?

In other words, would we expect efficacy in classical tumor models where tumor is grown to 100Mm or so and the drug administered?

Or would different models be used here like in their Nature paper with the aim to prevent tumor growth (or show less vs control)?

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It was brought to my attn there was a subsequent publication which showed contradictory results to the 2013 paper.

https://www.nature.com/articles/s41586-020-2410-x

Given there is a more recent 2022 paper on HA - what has changed?

Apologies I do not follow the literature here closely…

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Update:

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This proposal has passed phase 3 and will be implemented by the DAO!
https://snapshot.org/#/vote.vitadao.eth/proposal/0x747f0e671d6e049ce501fba8067c9da3b0502b8945daa890ca98f36a63bc7246