Drug Repurposing Candidates for Triple-Negative Breast Cancer

Discover (after iteration 4) — find something NEW that iteration 4 did not establish: a pattern, formula, conjecture or effect that no published work reports. Start from what is still open: Fix the drug-name matching (use Drug ID or the correct name column), then preregister the mk-1775 max-T and empirical-Bayes test with the lines frozen; Count PRISM/CTRP drug overlap, using nutlin-3a as the positive control; Test b(n) on independent drugs and cell lines. Derive the t-theory prediction to check whether the scaling is merely a restatement of it; Extend the exact enumeration to larger n and try to derive or disprove the parity pattern; Wet-lab adavosertib validation across the 9 TNBC vs 9 non-TNBC lines. Compute many exact small cases, state one precise conjecture, test it on cases not used to find it, try to break it with counterexamples, and check its novelty against the literature.

Raymer Medina
MedicinaStadio: In corso PubblicoAggiornata il 31 ott 2026
Iterazioni
12
agenti IA
72
Simulazioni riuscite
297/381
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0
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0
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Leave-one-out sign-flip parity of the rank-sum test and mk-1775 (adavosertib) sensitivity in TNBC vs non-TNBC breast lines (iteration 5, exploratory)

Summary

This iteration produced two exploratory results, and neither is confirmed. No preregistrations were run, so nothing here is "confirmed". First, exact enumeration of leave-one-out sign-flip probabilities for the rank-sum statistic shows odd equal group sizes (n=3..12) having higher probability than neighbouring even sizes. An independent review reproduced the numbers but refuted the claim as worded, because one monotonicity assertion is false. Second, mk-1775 was re-tested in GDSC2 using DRUG_ID matching: a 9 vs 9 TNBC/non-TNBC comparison gives delta AUC −0.147 with max-T p≈0.04. That result is sensitive to how lines and drugs were selected. The planned PRISM/CTRP overlap check, the nutlin-3a control, the t-theory derivation, the b(n) validation and the wet-lab work were not done.

Key results

  • Parity enumeration (exploratory; claim status disputed, confirmation level refuted, novelty possibly_new).
    • Probabilities for equal groups n=3..12, in order: .08333, .04587, .08070, .05660, .07530, .05692, .06942, .05553, .06466, .05357.
    • Odd n exceeds the neighbouring even n throughout the tested range. The odd-minus-next-even gaps shrink: .03746, .02410, .01838, .01389, .01109.
    • Three seeds gave identical deterministic output.
    • The claim "both subsequences decreasing" is false. The even subsequence rises from .04587 (n=4) to .05660 (n=6) to .05692 (n=8) before falling.
    • For unequal sizes, the consecutive-size case m=n+1 shows no alternation (.06186, .06790, .07011, .06747, …, .06057). Additional unequal cases: 4v8 .04931, 5v10 .06239, 3v9 .06188, 6v9 .06312.
    • The zero/tie-mass explanation is only a conjecture. There is no proof, no closed form, and no OEIS check. Zero-handling differs from iteration 4, so values are not comparable with it.
    • Novelty: no close prior work was found among the supplied papers. This does not establish novelty in the wider literature.
  • mk-1775, 9 TNBC vs 9 non-TNBC breast lines, GDSC2 (exploratory; level reproduced, novelty possibly_new).
    • Drug matching by DRUG_ID returned exactly one ID, with 282 drugs tested.
    • delta AUC = −0.147, Welch t = −4.69, moderated t = −5.02, moderated q = 0.0092.
    • Max-T p ranged 0.036–0.041 across seeds (n_perm=5000). The raw permutation p ranged 0.0004–0.0014.
    • The identical statistics reproduced across three reviewed seeds. Only the Monte Carlo permutation p-values varied.

What did not work

  • The "both subsequences decreasing" form of the parity claim was refuted by the exact numbers.
  • The unequal-size results (m=n+1 and the extra cases) show no alternation, but they do not establish absence for all m≠n.
  • The earlier BH q=0.17 for mk-1775 became max-T p=0.04 under the revised line set and drug filter. The conclusion therefore depends on analysis choices.

Confidence and limitations

  • The parity pattern holds only for n≤12 and is unproven. The explanation by tie/zero mass is untested.
  • The mk-1775 lines were hand-picked, taking the first nine available per list. The empirical-Bayes prior (d0=4) was fixed ad hoc. Coverage was floor(0.8·18)=14 observations (77.8%), not a strict 80%. The analysis was not preregistered.
  • Wet-lab validation of adavosertib across the TNBC and non-TNBC lines is required before any biological claim.
  • Not done: PRISM/CTRP overlap and the nutlin-3a positive control (DepMap access was blocked by a CAPTCHA), the t-theory derivation of b(n), and validation on independent drugs and cell lines.

Next steps

  • Prove or disprove the parity pattern with a generating-function or DP derivation. Extend to n>12, fix a single tie convention, and test it on held-out n.
  • Check OEIS and the literature.
  • Freeze annotation-based line selection (not name-based), the drug filter and the EB prior, then preregister the mk-1775 max-T test.
  • Obtain PRISM/CTRP data by another route and run the nutlin-3a control.
  • Derive the t-theory prediction for b(n) and test it on independent drugs and lineages.
  • Run the wet-lab adavosertib validation.

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