An integrated PDX para-clinical platform to improve molecularly guided targeted therapy.

<p>① Patients with muscle-invasive or advanced bladder cancer undergo transurethral or surgery resection. Some tumor specimens are implanted into NSG mice to establish PDXs. ② When the first PDXs (Passage 0 or P0) are established, some PDX specimens are implanted to more NSG mice to establish more PDXs (P1) while some other specimens are submitted for deep sequencing, including whole genome, exome and transcriptome sequencing. ③ Patients and mice carrying P1 PDXs receive the same primary treatment. ④ Computational biology is used to identify genetic aberrations in cancer cells. ⑤ Validation tests, such as direct sequencing, western blot, IHC and immunofluorescence staining, are performed to validate the genetic aberrations as identified in Step ④. ⑥ Because of the subcutaneous location and fast tumor growth in mice, tumor relapses in PDXs will occur sooner than that in human patients. Upon relapse, mice carrying PDXs will be treated with regimens A-D targeting 4 genetic alterations identified in Steps ④ and ⑤. In addition, serial biopsies can be performed during treatment. These biopsy specimens can be studied to decipher the secondary resistance mechanisms and guide the development of further therapy to overcome resistance. ⑦ Since only some of the genetic alterations are driver ones, some medications (Drug B and C) can induce response while PDXs do not respond to some other treatments (Drug A and D). ⑧ Upon cancer relapse in human patients, biopsy can be performed to validate the existence of genetic aberrations in the relapsed cancer, then the effective drug (Drug C) matching to the genetic aberrations in human cancers is used to treat relapsed cancer in patients. ⑨ Drug C can potentially be used while patients are in remission to cure or delay cancer recurrence.