Saturday, 29 July 2017

PARP combination therapy

Hello all,

I came across this article:

PARP inhibitor combination therapy

"Here, we summarise both the pre-clinical and clinical evidence for the utility of such combinations and discuss the future prospects and challenges for PARP inhibitor combinatorial therapies."
http://dx.doi.org/10.1016/j.critrevonc.2016.10.010

Does someone have experience regarding PARP combination therapy? I know this has been discussed before in other posts especially when a tumour is IDH1-mutated. In the article they also propose that MGMT methylation is positive factor for PARP therapy.

It would be interesting to see results from trials or hear personal experiences on PARP therapy.

All the best,
Juha

4 comments:

  1. The combination of PARP inhibitors plus temozolomide has a fascinating potential to sensitize tumors to TMZ, including tumors that are MGMT unmethylated and normally resistant to TMZ. 90% of DNA methylation events caused by TMZ are at the N7 position of guanine and N3 position of adenine and are normally non-toxic as these lesions are easily repaired by a process that requires PARP. Normally, it is mainly TMZ-induced methylation of guanine at position O6 that is toxic to cells, but these lesions account for only a minority of TMZ-induced DNA lesions and can be repaired by MGMT.

    PARP inhibitors that can trap PARP in PARP-DNA complexes can create a situation where these numerous N7 and N3 lesions (normally non-toxic) become toxic, in an MGMT independent manner (since MGMT cannot repair these lesions).

    An important thing to realize is that not all PARP inhibitors are equal in their ability to trap PARP in PARP-DNA complexes, which are crucial to the above mechanism. Olaparib and rucaparib are fairly effective in their PARP-trapping ability, but velaparib is a very weak PARP trapper. The novel PARP inhibitor BGB-290 might turn out to be the ideal PARP inhibitor for brain tumors, as it is said to have both strong PARP trapping activity, as well as significant brain penetration. In contrast, velparib has good brain penetration but weak PARP trapping activity, while olaparib has good PARP trapping activity but less than ideal brain penetration.

    The downside is that agents with strong PARP-trapping activity also have greater potential for toxicity in normal tissue. A phase 2 trial of rucaparib + temozolomide for metastatic melanoma showed that myelosuppression (toxicity to bone marrow) was a prominent side-toxicity. These toxicities have required the PARP inhibitor schedule or dose to be altered in combination trials.

    Sources:
    http://stm.sciencemag.org.sci-hub.cc/content/8/362/362ps17.full (PDF download, Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action)
    https://www.ncbi.nlm.nih.gov/pubmed/25758918 (Trapping Poly(ADP-Ribose) Polymerase)
    http://www.beigene.com/pipeline/clinical-candidates/bgb-290/
    https://clinicaltrials.gov/ct2/show/NCT02361723
    https://clinicaltrials.gov/ct2/show/NCT02660034

    ReplyDelete
  2. Thank you Stephen!

    We're now in situation where it seems evident that my sister's tumour has progressed (see more details here: http://btcocktails.blogspot.fi/2017/05/oligoastrocytoma-grade-3-progression.html).
    Her tumour is IDH1-mutated and MGMT-methylated. She has completed RT+TMZ and 12xcycles of TMZ (100mg/m2).
    The latest MRI result:"T2 signal of white matter shows increase at anterocranial side of the resection cavity. Tumour residuals seem unchanged."
    Her NO suggest to perform cytoreductive surgery on side of the resection cavity.

    After the surgery, the plan is to start PARP(olaparib)+TMZ.
    Our budget is limited, and after careful considerations and help of this community and other experts, we see PARP combination as a best bet.
    There are no promising clinical trials in Europe and vaccination strategy (DC+virus) doesn't seem that promising on recurrent tumours.

    There is a new olaparib trial opened for IDH1 mutated tumours: https://clinicaltrials.gov/ct2/show/NCT03212274

    Also, OPARATIC study has been ongoing for a quite a long time (olaparib + TMZ):
    https://clinicaltrials.gov/ct2/show/NCT01390571


    br,
    Juha


    ReplyDelete
    Replies
    1. It would be worthwhile to start considering P-glycoprotein inhibitors to take along with olaparib, seeing the olaparib is a P-glycoprotein substrate which could limit its penetration across the blood-brain barrier and uptake by tumor cells.

      Verapamil, and fluoxetine or sertraline are possibilities, as well as epigallocatechin gallate (EGCG).

      http://astrocytomaoptions.com/the-blood-brain-barrier/
      https://www.ncbi.nlm.nih.gov/pubmed/11853888 (Inhibition of the multidrug resistance P-glycoprotein activity by green tea polyphenols.)
      https://www.ncbi.nlm.nih.gov/pubmed/24700236 (PARP Inhibitors as P-glyoprotein Substrates)
      http://www.pnas.org/content/112/27/8409.abstract (Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer)

      Delete
  3. Thanks again Stephen! We'll certainly push for P-glycoprotein inhibitors in addition to PARP+TMZ combo when next seeing the oncologist.

    br,
    Juha

    ReplyDelete