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

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.

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.

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.

IP-NFT Ownership

Collaborators (Vera Gorbunova) - 10%
Molecule AG - 10%
VitaDAO – 10%
Matrix Pharma - 70%

The capital structure (equity ownership) of Matrix Pharma after the Seed Financing will be as follows:

Collaborators (Vera Gorbunova): 15%
Investors (VitaDAO): 70%
Options pool for future team members: 15%

VitaDAO is a holder of Matrix Pharma equity in addition to direct ownership of the IP-NFT, to facilitate fractionalization with help by technology partner Molecule AG.

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 - Matrix Pharma Board

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.

Lutz Kummer, PhD

Lutz, Ph.D, is a biochemist by training and Head of R&D at Molecule with a passion for creating, launching, and building organizations to deliver multiple life-changing therapies. He was co-founder and CSO of G7 Therapeutics until it was sold to Sosei Heptares. He subsequently served as scientific leader of the Swiss subsidiary of Sosei Heptares. He continued to broaden his horizon in the life science and pharma ecosystem as fellow for Nextech Invest, a leading oncology focused venture firm, and as health industry expert at PricewaterhouseCoopers (PwC). Further, he served as co-founder and VP Operations and Development for the immuno-oncology start-up InCephalo.

Sebastian Brunemeier

Sebastian A. Brunemeier is a biotech VC and company builder focused on longevity & regenerative medicine. He is Co-Founder and General Partner of Healthspan Capital, and CEO and Founder of ImmuneAGE Pharma (stealth), focused on immune system rejuvenation. Over the last 5 years, he has co-founded 4 longevity biotech (“LongBio”) companies with a total equity value of > $600M. He was Co-Founder and Chief Investment Officer at Cambrian Biopharma, Co-Founder and COO of Samsara Therapeutics, and Principal at Apollo Health Ventures (the first and largest aging- focused venture capital fund in the world with $200M AUM). Altogether, these organizations have raised ±$400M in the last 4 years. He was a Fulbright Fellow on the biology of aging, a Skaggs- Oxford Scholar at the Scripps Research Institute, and a SENS Foundation Scholar at the Buck Institute for Research on Aging. His education includes partial DPhil (PhD) training in biochemistry of aging at the University of Oxford as a Clarendon Scholar, a Master’s in Life Science Business Management and Molecular Neuroscience from the University of Amsterdam as an Amsterdam Excellence Scholar. He served as trustee of the British Society for Research on Aging, a mentor at The New York Academy of Sciences, and as an advisor or board member to: VitaDAO/Molecule.to, Equator Therapeutics, Revivo Therapeutics, Shift Biosciences, Deciduous Therapeutics, and McKinsey & Company.

Tim Peterson, PhD

Dr. Peterson is an MIT- and Harvard-trained faculty member at Washington University in St. Louis (a.k.a. WashU or WUSTL) School of Medicine (WUSM). WUSM is a perennially top-five US institution in terms of research funding and publishing and is tied to 19 Nobel Prize winners since its founding in 1909. Over his 15-year research career, Dr. Peterson has published in Nature, Science, and Cell and their affiliated journals and has received grant funding from the NIH, American Diabetes Association, the Nathan Shock Aging Center, Amazon Web Services amongst others. Dr. Peterson’s focus on longevity started with his PhD at MIT. At MIT, he made multiple seminal discoveries on rapamycin and the pathway it targets the mTOR pathway. Rapamycin and mTOR are arguably the most widely validated longevity therapy and pathway, respectively. At Harvard, Dr. Peterson trained under Erin O’Shea, PhD who now leads HHMI. There Dr. Peterson focused on longevity drug mechanisms, e.g., on the osteoporosis drug bisphosphonates and the diabetes drug metformin, which he has since carried with him into his academic lab and companies. In addition to his role at WashU and BIOIO, Dr. Peterson is a co-founder of Healthspan Technologies, which is developing mRNA lipid nanoparticle (LNP)-based therapeutics with a focus on vaccines for aging-accelerating infectious agents. Prior to his professional career, Dr. Peterson trained with the US Rowing Team from 1999-to 2001.

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

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

2 Likes

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.

5 Likes

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.

7 Likes

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

1 Like

Okay the poll should be corrected. Apologies for any confusion

1 Like

Thanks @tylerstahl

@everyone please vote again

1 Like

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.

1 Like

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.

1 Like

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?

2 Likes

Thoughts on traunching this into 3x 100k phases?

1 Like

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

2 Likes

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

2 Likes

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

1 Like