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Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity.

Catenacci DV - Mol Oncol (2014)

Bottom Line: The promise of 'personalized cancer care' with therapies toward specific molecular aberrations has potential to improve outcomes.These issues have become hurdles to advancing cancer treatment outcomes with novel molecularly targeted agents.Finally intra-patient heterogeneity through time may be addressed by serial biomarker assessment at the time of tumor progression.

View Article: PubMed Central - PubMed

Affiliation: University of Chicago Medical Center, Department of Medicine, Section of Hematology & Oncology, 5841 S. Maryland Avenue, MC2115, Chicago, IL 60637, USA. Electronic address: dcatenac@medicine.bsd.uchicago.edu.

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The “run-away 18-wheeler truck” metaphor of cancer and current therapeutic strategies. ©Ion Medical Designs, LLC 2014. (A) In the untreated scenario, cancer is like a run-away truck without brakes (loss of tumor suppressor) quickly and inappropriately accelerating down a hill. (B) In an attempt to slow down the truck (cancer cell), altering the slope (tumor environment) to ‘uphill’ has been employed {eg. anti-angiogenesis}. (C) Stopping the driver from pushing the gas pedal {targeted inhibition towards the function of the oncogenic genomic driver} may relieve the inappropriate acceleration {eg. trastuzumab for HER2 gene amplification}, if only temporarily until another mechanism (inherent or acquired) to maintain the acceleration stimulus (oncogenic driver) moves to replace it. (D) Although loss of any back wheel (downstream effector) will likely not slow the truck given the presence of numerous wheels (redundant parallel escape signals), some wheels downstream can be critical, like when inducing a flat front tire (critical downstream hub) {eg. inhibition of DNA synthesis: classic cytotoxics; or inhibition of key protein: estrogen/androgen receptor antagonists}. (E) Reversing mechanisms of police (immune) evasion can re-establish the ability to recognize and eliminate the abnormal ‘speedy truck’ {immunomodulation}. A combination of the strategies in (B–E) may be optimal to slow with significant magnitude and duration.
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Figure 1: The “run-away 18-wheeler truck” metaphor of cancer and current therapeutic strategies. ©Ion Medical Designs, LLC 2014. (A) In the untreated scenario, cancer is like a run-away truck without brakes (loss of tumor suppressor) quickly and inappropriately accelerating down a hill. (B) In an attempt to slow down the truck (cancer cell), altering the slope (tumor environment) to ‘uphill’ has been employed {eg. anti-angiogenesis}. (C) Stopping the driver from pushing the gas pedal {targeted inhibition towards the function of the oncogenic genomic driver} may relieve the inappropriate acceleration {eg. trastuzumab for HER2 gene amplification}, if only temporarily until another mechanism (inherent or acquired) to maintain the acceleration stimulus (oncogenic driver) moves to replace it. (D) Although loss of any back wheel (downstream effector) will likely not slow the truck given the presence of numerous wheels (redundant parallel escape signals), some wheels downstream can be critical, like when inducing a flat front tire (critical downstream hub) {eg. inhibition of DNA synthesis: classic cytotoxics; or inhibition of key protein: estrogen/androgen receptor antagonists}. (E) Reversing mechanisms of police (immune) evasion can re-establish the ability to recognize and eliminate the abnormal ‘speedy truck’ {immunomodulation}. A combination of the strategies in (B–E) may be optimal to slow with significant magnitude and duration.

Mentions: Continuing with the EGFR example, a ‘driver vs wheel’ metaphor of a ‘run-away 18-wheeler truck’ can help to conceptualize the current appreciation of inter-patient heterogeneity of molecular ‘oncogenic drivers’ (the gas pedal) and loss of tumor suppressors (the brakes) (Figure 1A). When EGFR is the genomic ‘driver’ of a tumor (ie. EGFR mutation or EGFR amplification; in appropriately ‘pushing the gas pedal’), using targeted inhibition towards that driver generally has resulted in significantly improved clinical outcomes in that patient subset, (Petty et al., 2014; Zhang et al., 2013; Zhou et al., 2011) albeit until development of resistance with consequent progression (Figure 1C). On the other hand, in settings when EGFR is ‘over-expressed’ without genomic activation, or even less impressively merely ‘expressed’, similar to any of hundreds to thousands of other proteins in a tumor, EGFR may only be one of many wheels (downstream effectors) on the truck (cancer cell) (Figure 1A). Therefore, it is not critical and is easily expendable if neutralized, with other wheels (parallel escape signaling) taking up the slack. (Waddell et al., 2013; Lordick et al., 2013a).


Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity.

Catenacci DV - Mol Oncol (2014)

The “run-away 18-wheeler truck” metaphor of cancer and current therapeutic strategies. ©Ion Medical Designs, LLC 2014. (A) In the untreated scenario, cancer is like a run-away truck without brakes (loss of tumor suppressor) quickly and inappropriately accelerating down a hill. (B) In an attempt to slow down the truck (cancer cell), altering the slope (tumor environment) to ‘uphill’ has been employed {eg. anti-angiogenesis}. (C) Stopping the driver from pushing the gas pedal {targeted inhibition towards the function of the oncogenic genomic driver} may relieve the inappropriate acceleration {eg. trastuzumab for HER2 gene amplification}, if only temporarily until another mechanism (inherent or acquired) to maintain the acceleration stimulus (oncogenic driver) moves to replace it. (D) Although loss of any back wheel (downstream effector) will likely not slow the truck given the presence of numerous wheels (redundant parallel escape signals), some wheels downstream can be critical, like when inducing a flat front tire (critical downstream hub) {eg. inhibition of DNA synthesis: classic cytotoxics; or inhibition of key protein: estrogen/androgen receptor antagonists}. (E) Reversing mechanisms of police (immune) evasion can re-establish the ability to recognize and eliminate the abnormal ‘speedy truck’ {immunomodulation}. A combination of the strategies in (B–E) may be optimal to slow with significant magnitude and duration.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4402102&req=5

Figure 1: The “run-away 18-wheeler truck” metaphor of cancer and current therapeutic strategies. ©Ion Medical Designs, LLC 2014. (A) In the untreated scenario, cancer is like a run-away truck without brakes (loss of tumor suppressor) quickly and inappropriately accelerating down a hill. (B) In an attempt to slow down the truck (cancer cell), altering the slope (tumor environment) to ‘uphill’ has been employed {eg. anti-angiogenesis}. (C) Stopping the driver from pushing the gas pedal {targeted inhibition towards the function of the oncogenic genomic driver} may relieve the inappropriate acceleration {eg. trastuzumab for HER2 gene amplification}, if only temporarily until another mechanism (inherent or acquired) to maintain the acceleration stimulus (oncogenic driver) moves to replace it. (D) Although loss of any back wheel (downstream effector) will likely not slow the truck given the presence of numerous wheels (redundant parallel escape signals), some wheels downstream can be critical, like when inducing a flat front tire (critical downstream hub) {eg. inhibition of DNA synthesis: classic cytotoxics; or inhibition of key protein: estrogen/androgen receptor antagonists}. (E) Reversing mechanisms of police (immune) evasion can re-establish the ability to recognize and eliminate the abnormal ‘speedy truck’ {immunomodulation}. A combination of the strategies in (B–E) may be optimal to slow with significant magnitude and duration.
Mentions: Continuing with the EGFR example, a ‘driver vs wheel’ metaphor of a ‘run-away 18-wheeler truck’ can help to conceptualize the current appreciation of inter-patient heterogeneity of molecular ‘oncogenic drivers’ (the gas pedal) and loss of tumor suppressors (the brakes) (Figure 1A). When EGFR is the genomic ‘driver’ of a tumor (ie. EGFR mutation or EGFR amplification; in appropriately ‘pushing the gas pedal’), using targeted inhibition towards that driver generally has resulted in significantly improved clinical outcomes in that patient subset, (Petty et al., 2014; Zhang et al., 2013; Zhou et al., 2011) albeit until development of resistance with consequent progression (Figure 1C). On the other hand, in settings when EGFR is ‘over-expressed’ without genomic activation, or even less impressively merely ‘expressed’, similar to any of hundreds to thousands of other proteins in a tumor, EGFR may only be one of many wheels (downstream effectors) on the truck (cancer cell) (Figure 1A). Therefore, it is not critical and is easily expendable if neutralized, with other wheels (parallel escape signaling) taking up the slack. (Waddell et al., 2013; Lordick et al., 2013a).

Bottom Line: The promise of 'personalized cancer care' with therapies toward specific molecular aberrations has potential to improve outcomes.These issues have become hurdles to advancing cancer treatment outcomes with novel molecularly targeted agents.Finally intra-patient heterogeneity through time may be addressed by serial biomarker assessment at the time of tumor progression.

View Article: PubMed Central - PubMed

Affiliation: University of Chicago Medical Center, Department of Medicine, Section of Hematology & Oncology, 5841 S. Maryland Avenue, MC2115, Chicago, IL 60637, USA. Electronic address: dcatenac@medicine.bsd.uchicago.edu.

Show MeSH
Related in: MedlinePlus