ROLE OF UNDERSTANDING THE "LAWS OF NATURE" IN CELLULAR BIOLOGY.

Although cells pathways have now been described, harvesting this information with no discrimination will not lead to a cure in a timely fashion.  There is a perception that combining therapeutic agents will always be better than using one agent.  Extremists have even believed that throwing to the patient a kitchen sink of medications could yield better results.  And time and again these approaches failed to show an improvement of survival.
One of the most memorable example is the CHOP story which led to keeping CHOP as standard of care for lymphoma over at least 2 decades.  The CHOP reign ended with the Arrival of Rituxan, a target therapy.
What we have learned over the years is that there could be minimal or no improvement in attacking the cell by focusing  on one pathways.  Attacking the cell on different steps of the pathway works only if that Pathway has the DRIVER mutation.  Otherwise the cell will easily escape the attack using its inter-connections, loopholes, redundancy and heterozygosity mechanism.  The NF-kB would allow adaptative transformation.
For a clear clear improvement in effect, combined drug should affect 2 different pathways as they relate to different laws of Nature:
1. DNA Break  (compromising cell division) include P53 arrest
2. Microtubule Break (compromising Mitosis, cell division, cell migration, and Embryogenesis) lead directly to Caspase in the Mitochondia
3. Receptors (impairment of signal generation and amplification and Angiogenesis) Growth factors, cyclins, anti VGEF, FGFR,
4. Impairment of Amplification  (blocking signal amplification, includes Proteasome inhibitor which dampen signal transduction by harvesting an overall feedback-negative effect of ubiquitinated compounds )
5. Impairment of Differentiation (RAS)
6. Immune Modulation
7. Opening Hidden traps to Apoptosis or program cell death (FOXO3, histone deacetylase)
8.  Impairing Migration to block Metastasis and cellular sensing of its environment lead to Anoikis.

Most combination fail because they focus on 1 of the 8 aspects.

Taxol carboplatin has been good to us because of the Microtubule and DNA.  This combination works better in standard rate of cell division.  In higher rate, breaking the DNA faster with Etopside-Cisplatin prove to be beneficial (small cell lung cancer, c-MYC is the amplifier like in Burkitt).  But it is until you involve the Mirotubule that you see benefit such as in Gastric cancers.  Adding 5-FU based product did not show benefit particularly in Gastric cancer.
CAF in Breast cancer was incremental because of DNA breakage but also because of the Adriamycin effect of cellular membrane which disturb the Microtubule at this location.

DRUGS AFFECTING one each path generally surprised us

1 here are CISPLATIN, etoposide,Oxaliplatin
2. Taxanes
3. Avastin, Erbitux
4. Velcade, Afinitor, Cabozantinib
5. anti-BRAF, anti-Hedgehog, Ibrutinib
6. Interferon, Rituxan
7. M-tor, Dasatinib
8. Anti-Integrins

 significant combinations should cross these 8 lines! And choice should be based on
1. Solid Vs Hematologic disease
2. Knowledge of Driver Mutations if any
3. Knowledge of driver pathways if any
4. knowledge of Resistance mechanism if any
5. knowledge of preponderant specific Receptor
6. Importance of Cyclins and growth factors
7. Exclusive Seeding niche if any