Could cancer drugs help with HD?

Posted on by raytruant

Blog post by Dr. Tamara Maiuri

I would like to start this post by saying that the ideas below are PURELY SPECULATIVE at this point. But I’m excited about them and feel they definitely warrant further investigation.

So here’s the deal: In a study funded by the HDSA Berman/Topper fellowship, we have found that the huntingtin protein interacts with proteins modified by poly ADP ribose (PAR), and that PAR levels are elevated in cells from HD patients.

 

What is PAR?

PAR is a branched chain-like molecule that acts as a recruitment scaffold for DNA repair proteins. It’s made by an enzyme called poly ADP ribose polymerase (PARP) upon DNA damage (we and others also see elevated levels of DNA damage in HD patient cells [1–3]).

 

What is PARP?

There are several PARP enzymes, but let’s concentrate on PARP1 for now. PARP1 is a major player in the DNA damage response.

PARP1 uses a building material called NAD+ to generate the branched PAR chains that recruit DNA repair factors. The problem is, NAD+ is needed for other things in the cell, especially for converting food into energy. So PARP1 activity is great for a quick response to clear up some DNA damage, but if the damage is too great (or if it’s prolonged), then energy levels in the cell get depleted.

 

PARP hyper-activation

There are several negative consequences if PARP activity goes on too long. Let’s compare a list of these negative consequences to what is seen in HD models and patients (NB: these phenotypes are very much interrelated):

PARP hyper-activation phenotypes

HD phenotypes
ATP depletion [4–7] ATP depletion [8–13]
Mitochondrial dysfunction [14–17] Mitochondrial dysfunction (reviewed in [18])
Energy crisis [19,20] Energy crisis (reviewed in [21])
Cell death (through parthanatos) [22,23] Cell death through apoptosis, necrosis (parthanatos not yet tested) (reviewed in [24])
Neuroinflammation [25–29] Neuroinflammation [30–32]
Transcriptional and chromatin changes (reviewed in [33]) Transcriptional and chromatin changes (reviewed in [34,35])
Autophagy and protein clearance (reviewed in [36,37]) Autophagy and protein clearance (reviewed in [38,39])

Just looking at this list, even if we had no indication that PAR is dysregulated in HD, I would say it’s worth looking into! Turns out, PARP hyper-activation has been linked to other neurodegenerative diseases (reviewed in [40]), most recently Parkinson’s [41].

 

The good news

The cancer field has done decades of work to understand how to inhibit PARPs. I didn’t think this would be much use to us in the HD field, since the point of cancer drugs is to KILL TUMOUR CELLS, while we are looking for drugs to KEEP NEURONS ALIVE.

I was disabused of this notion when I read a very nice review article called Opportunities for the repurposing of PARP inhibitors for the therapy of non-oncological diseases [42]. The article recommends that for chronic, non-oncological indications where there is a significant unmet need, we should consider taking PARP inhibitors to trial.

 

Criteria for deciding whether to try PARP inhibitors for a non-oncological indication

Q: Is there preclinical data demonstrating the efficacy of PARP inhibition in clinically relevant preclinical models?
A: Not yet, but:
  • PARP inhibition is beneficial in R6/2 mice [43,44]
  • Truant lab student Carlos Barba is currently testing PARP inhibition in TruHD cells (and STHdh cells, although not as clinically relevant)
  • We have also asked Chris Ross’s lab to test PARP inhibition in neurons expressing the huntingtin 1-586 fragment (this is an overexpression system, but at least it is in neurons)

 

Q: Is there human data confirming activation of PARP in the target organ?
A: Not yet, but:

 

Q: Would the duration of treatment be short, to limit potential side effects?
A: Unfortunately, no. But intermittent administration (“drug holidays”) could be an option.

 

Q: Are existing therapeutic alternatives insufficient?
A: Yes.

 

Q: Is HD severe enough to justify an attempt for novel therapies, especially in light of the potential “genotoxic baggage” that comes with PARP inhibition?
A: Hell yes.

 

Q: Would a trial be logistically feasible?
A: The HD community has proven that they are very capable of designing, recruiting, and running clinical trials.

Preclinical studies should:

  • Use the drug that will eventually be trialed
  • Use the most clinically relevant models
  • Document the drug effects on DNA and chromosomal integrity (for ideas about safety)

The Truant lab works with preclinical systems. We are doing our best to make sure these preclinical studies are done properly so they can be most informative going forward. All of my results will be shared openly through this blog and our Zenodo Community. I welcome any comments or suggestions about how we might test PARP and PAR in HD systems. And now, back to the bench!

 

References

  1. Maiuri T, Mocle AJ, Hung CL, Xia J, van Roon-Mom WMC, Truant R. Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex. Hum Mol Genet. 2017;26: 395–406.
  2. Askeland G, Dosoudilova Z, Rodinova M, Klempir J, Liskova I, Kuśnierczyk A, et al. Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington’s disease patients. Sci Rep. 2018;8: 9817.
  3. Castaldo I, De Rosa M, Romano A, Zuchegna C, Squitieri F, Mechelli R, et al. DNA damage signatures in peripheral blood cells as biomarkers in prodromal huntington disease. Ann Neurol. 2019;85: 296–301.
  4. Sims JL, Berger SJ, Berger NA. Poly(ADP-ribose) Polymerase inhibitors preserve nicotinamide adenine dinucleotide and adenosine 5’-triphosphate pools in DNA-damaged cells: mechanism of stimulation of unscheduled DNA synthesis. Biochemistry. 1983;22: 5188–5194.
  5. Berger NA, Sims JL, Catino DM, Berger SJ. Poly (ADP-ribose) polymerase mediates the suicide response to massive DNA damage: studies in normal and DNA-repair defective cells. Princess Takamatsu Symp. 1983. pp. 219–226.
  6. Alano CC, Garnier P, Ying W, Higashi Y, Kauppinen TM, Swanson RA. NAD+ depletion is necessary and sufficient for poly(ADP-ribose) polymerase-1-mediated neuronal death. J Neurosci. 2010;30: 2967–2978.
  7. Ha HC, Snyder SH. Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc Natl Acad Sci U S A. 1999;96: 13978–13982.
  8. Mochel F, Durant B, Meng X, O’Callaghan J, Yu H, Brouillet E, et al. Early alterations of brain cellular energy homeostasis in Huntington disease models. J Biol Chem. 2012;287: 1361–1370.
  9. Hung CL-K, Maiuri T, Bowie LE, Gotesman R, Son S, Falcone M, et al. A Patient-Derived Cellular Model for Huntington’s Disease Reveals Phenotypes at Clinically Relevant CAG Lengths. Mol Biol Cell. 2018; mbcE18090590.
  10. Milakovic T, Johnson GVW. Mitochondrial respiration and ATP production are significantly impaired in striatal cells expressing mutant huntingtin. J Biol Chem. ASBMB; 2005; Available: http://www.jbc.org/content/280/35/30773.short
  11. Trettel F, Rigamonti D, Hilditch-Maguire P, Wheeler VC, Sharp AH, Persichetti F, et al. Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells. Hum Mol Genet. 2000;9: 2799–2809.
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