NF-kB PATHWAY AND CANCER SURVIVAL, (Inhibitor: Parthenolide)
All refractory cancers seem to have one strong characteristic.  They survive even when the kitchen sink is thrown at them.  By kitchen sink, I mean all kinds of combination chemotherapy.  In fact, times and again we have seen that only one medication turns out to be working as comparative studies end up showing equivalency between a combination therapy Vs a monotherapy.  The story of DTIC in Melanoma is an example that combination therapy Vs DTIC alone, there was no difference in survival.  The reasons for this drug resistance is multiple.  The cell may have an MDR (Multiple drug Resistance) protein that effectively shut down cellular processes to the various drugs, but can't mount an elective resistance to DTIC.  Or the cell may activate its NF-kB pathways to survive.

As cells live their lives in our body they come in contact with all kinds of neighbors and enemies, including drugs constantly thrown around in our body.  The cells register the invasion, exposure or attack and send the message through a pathway of survival called NF-kB.  Signals from this pathways are interpreted quickly and our body modulate the attack in the general sense of survival.  To achieve this, some transcription genes are amplified to make more blockers to the invasion (ie. Bcl-2), some transcription genes are shut down to reduce susceptibility to the attack.  The NF-kB pathway is in this a critical pathway of adaptation to life.  It is central to all immune diseases, it is critical to resistance to diseases, it is the force to reckon with when you give a drug to treat anything including cancer.  You got to stop NF-kB from working effectively to achieve your goal.  Because, unlike the MDR and Flippase which are determined in their place of action and mechanism, this pathway is constantly searching for an answer against therapy by modulating various transcription factors!  You see here now why attempts to target this pathway are so important.

To assure versatility in its action, NF-kB knows it cannot do it on its own, it "cross-talks" to many other pathways and important molecules.  One of which is the STAT3 for rapid transcription of whatever protein is needed  to decrease Apoptosis and protect the cell.  NF-kB a constant, moving and changing fighter which will do anything to decrease activities that can lead to death of the cell.  So far Phosphorylating it has been with limited success.  May be its inhibitors need to be given with Velcade or Cabozantinib.

Allez Hop! another mighty combination to try in a difficult disease has been created!
Taxol/cisplatin/Velcade and Parthenolide  for triple negative Breast cancer!
(Instead of Parthenolide, may be IL-2 could work)