A concept for developing a non-invasive mutant IDH diagnostic test

 In January, 2024, and after thinking more about therapeutic advances with the potential to target mutated Isocitrate Dehydrogenase present in some brain cancers, I emailed a diverse group of experts with some thoughts on a potential future non-invasive diagnostic test that might help confirm the presence of IDH mutations.  I contacted people unknown to me, but whose names I had found on a variety of published material, in hopes that they might share it with others who could determine whether there might be future value here.  Now, I'm posting it to this blog in hopes that others with associated interest might one day find it and be able to assess the ideas viability.  Below, I share what I sent as a lengthy and unsolicited email.


Sent on Monday, January 15, 2024:

I write today with a hope of reaching experts who might validate or refute a future model I envision for a non-invasive and potentially simple diagnostic test to detect the presence of IDH mutations associated with Gliomas, AML and other cancers (1) (2) (3) (4) (below, I use mIDH to refer broadly to the group of identified mutations in both IDH1 and IDH2, and conclude with a list of numbered references).  I describe a possible future vision with a rudimentary description of the work needed, and hope to inspire interest.  While I have not found anything published comparable to what I described below, I'm unlikely to be the first to think of this approach and intend no duplication of existing work, but wanted to share in case it could spark further innovation.  If you find this interesting or intriguing, I ask you to forward to any who might share an interest in further exploring the concept.

Brief background and inspiration for my vision

I’m no expert in this space, but with a B. Sc. in Biochemistry from McMaster University and a 23-year career in generic pharmaceutical product development, I’m now fourteen months past a craniotomy and right fronto-temporal lobectomy that removed about a half cup of Grade II Oligodendroglioma.  My education and work background fuels my curiosity in learning about cancers like mine and I’m fascinated by what I’m still learning about the role of mIDH and its role as a potential diagnostic and therapeutic target.  I suspect this background will be familiar to you, and it is what inspires my thoughts on further related opportunity.

In 2017, a suite of pre-clinical discovery assays that can be used to assess mIDH inhibitor efficacy were shared (5), focusing on quantitative measurement of the oncometabolite D-2-hydroxyglutarate (2-HG) produced by cells cultured in media and in the presence of diverse competitive inhibitors of mIDH.  The competitive inhibitors are described briefly by Urban et al., and I presume are patented for their therapeutic potential.  In 2020, the FDA granted Breakthrough Therapy designation while anticipating Vorasidenib and companion Oncomine Precision Assay (6) diagnostic test to provide rapid genomic profiling from a biopsy sample, allowing a patient’s care team to rapidly determine whether an mIDH inhibitor like Vorasidenib might be a suitable therapeutic approach.  These and future diagnostic and therapeutic avenues offer hope and promise, but I think there’s more to explore here.

My Vision and anticipated challenges

I envision a related and understandably more complex development model where instead of assessing competitive inhibitors, we might design other chemically diverse alterations of Isocitrate to use as a diagnostic tool that might reduce the need for an invasive biopsy.  I believe it should be feasible to design molecules that utilize the unique conformation of the mIDH protein structure and its altered metabolic activity in producing 2-HG to instead produce a unique and detectable metabolite that would then signal a mutant IDH phenotype somewhere in a patient’s body.  This won’t be simple, so I describe some anticipated challenges.

Instead of inhibiting mIDH, an appropriately designed molecule might be metabolized by mIDH to produce a unique detectable metabolite that should not otherwise be found in vivo, whether by wild-type IDH metabolism or other hepatic or extrahepatic metabolism.  I understand this will require a non-trivial effort in identifying potential molecules and conducting necessary screening.  I expect it to be challenging to find a molecule that could be metabolized by just a small cohort of cells with mIDH where the metabolite is then re-distributed out of the cells for eventual elimination.

Candidate molecule identification and screening would benefit from physiologically based pharmacokinetic modeling (PBPK) (7) and/or similar in-silico predictions of activity and metabolites in connection with mIDH and toxicity studies for it and its metabolites (including non-mIDH metabolism outcomes).  After identifying a likely mIDH-produced metabolite – expected to occur in near-zero quantities in pre-symptomatic patients – the next step of identifying appropriate diagnostic assay will be a notable challenge.  Options like detecting via blood test, urinalysis, breath biopsy or other could be selected based on the understood elimination route of the metabolite and anticipated limits of detection of a given analysis.  I anticipate it will require high precision analytical instruments common in diagnostic laboratories, but could be made readily accessible through the right companion tools or kits for such labs.

I foresee a diagnostic test that could begin with a patient being dosed with a suitable aliquot of this specifically designed molecule, before returning to a lab after an appropriate duration to provide the required sample and allow for optimal metabolite detection.  A suitably designed diagnostic assay could begin as a binary ‘yes / no’ result that could only confirm the presence of mIDH somewhere, rather than being able to locate or quantify the extent of any associated cancer.

A stick-figure model to build a Business Case

Globally, more than 300,000 new cases of brain cancer have been recorded each year for the past decade (8) – this figure is for brain cancer alone, without considering incidence of AML or other potentially mIDH-associated cancers.  Patients today often approach their care team when symptoms arise or after a serious and unignorable event, and where an MRI may point to a lesion that cannot be fully identified without biopsy or resection.  In some cases, a patient may have a small growth where serial monitoring is acceptable before biopsy and/or resection, such that a care team has no ability to further characterize and fully diagnose the cancer type and sub-type.

If a non-invasive diagnostic test were available, there would be percentage of patients and care teams who could benefit from confirming mIDH presence.  If presence of mIDH were confirmed, it should be possible to prescribe an mIDH inhibitor earlier in disease progression, delaying the need for surgery and further prolonging a patient’s quality of life.  It ought to be possible with appropriate assumptions to predict the benefit to healthcare systems by offering a lower rate of highly invasive surgeries by making mIDH inhibitors available earlier to patients who could benefit from their anticipated longer Progression Free Survival and Time To Next Intervention.

If a developed non-invasive diagnostic test’s risk profile were proven to be sufficiently outweighed by the benefits offered from earlier non-invasive therapy, the diagnostic test ought to be approvable and adopted in a way that should recover the costs of discovering, developing, and validating such a test while also providing broad healthcare savings.

I know this high-level description of a business case lacks any real figures or financial projections and is fully reliant on the proposal being feasible.  Rather than a full proposal with NPV and ROI, I’m just sharing preliminary thoughts on why this concept could make for a compelling investment in the time and resources that would be required if.  I am doubtless that experts closer to the work needed should be able to either confirm my intuition on this, or to demonstrate some gaps or flaws I have overlooked, which is why I’m sharing with each of you I’ve included on this email

I thank you for your time spent reading this unconventional and lengthy email, and hope that you might share with any colleagues you feel might be interested in pursuing this where I am unable to.  With my sincere thanks,

 

Stuart Selby  |  Toronto, Ontario, Canada   |  Twitter / X: @StupertInTO

 

 

References Cited

  1. IDH1 and IDH2 mutations in gliomas. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. 8, N Engl J Med, Vol. 360, pp. 765–73.  doi: 10.1056/NEJMoa0808710
  2. IDH Mutations in AML Patients; A Higher Association with Intermediate Risk Cytogenetics. El-Nahass, Yasser H., et al. 2019, Clinical Lymphoma, Myeloma & Leukemia, Vol. 19.  doi: 10.1016/j.clml.2019.07.073
  3. IDH mutations in glioma and acute myeloid leukemia. Dang, Lenny, Jin, Shengfang and Su, Shinsan M. 9, 2010, Trends in Molecular Medicine, Vol. 16, pp. 387-397.  doi: 10.1016/j.molmed.2010.07.002
  4. Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Yen, Katharine E., et al. 49, 2010, Oncogene, Vol. 29, pp. 6409-6417.  doi: 10.1038/onc.2010.444
  5. Assessing inhibitors of mutant isocitrate dehydrogenase using a suite of pre-clinical discovery assays. Urban, Daniel J., et al. 1, 2017, Scientific Reports, Vol. 7, p. 12758.  doi: 10.1038/s41598-017-12630-x
  6. Tucker, Nichole. Targeted Oncology. FDA Grants Breakthrough Therapy Designation to Vorasidenib CDx in IDH1/2-Mutant Low-Grade Gliomas. [Online] June 15, 2020. [Cited: 1 15, 2024.] https://www.targetedonc.com/view/fda-grants-breakthrough-therapy-designation-to-vorasidenib-cdx-in-idh1-2-mutant-low-grade.
  7. Physiologically based pharmacokinetic (PBPK) modeling and simulation: applications in lead optimization. Peters, Sheila Annie, Al, Ungell and Dolgos, Hugues. 4, 2009, Current Opinion in Drug Discovery & Development, Vol. 12, p. 509.  PMID: 19562647
  8. International patterns and trends in the brain cancer incidence and mortality: An observational study based on the global burden of disease. Ilic, Irena and Ilic, Milena. 7, s.l. : Cell Press, July 13, 2023, Heliyon, Vol. 9.  doi: 10.1016/j.heliyon.2023.e18222

Comments

Post a Comment